Postoperative nomogram predicting risk of recurrence after radical hysterectomy for early-stage cervical cancer.

OBJECTIVE: The aim of this study was to develop a nomogram for predicting the 5-year disease-free survival (DFS) after radical hysterectomy for early-stage cervical cancer. PATIENTS AND METHODS: An institutional database of 275 consecutive patients treated at Seoul National University Hospital for stage I to stage IIA cervical cancer was used to develop a nomogram based on Cox proportional hazards regression model. The developed nomogram was internally validated with bootstrapping, and performance was assessed by concordance index and a calibration curve. External validation was also performed using an independent data set of patients from Asan Medical Center. RESULTS: From Cox regression analysis, disease stage, number of positive lymph nodes, parametrial involvement, and depth of invasion were identified as independent risk factors for disease recurrence (P < 0.05). The nomogram incorporating these factors appeared to be accurate and predicted the outcomes better than the International Federation of Gynecology and Obstetrics stage alone (concordance index, 0.858 compared with 0.719; P = 0.001). When applied to a separate validation set, the nomogram also showed similar predictive accuracy (concordance index, 0.879). CONCLUSION: We have developed a nomogram that can predict the recurrence risk in patients with early-stage cervical cancer after surgery, which was internally and externally validated.

Expression of MMP-2, MMP-9, and urokinase-type plasminogen activator in cervical intraepithelial neoplasia.

Matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) are important factors for cancer invasion and metastasis, degrading the extracellular matrix. They are also associated with angiogenesis. Angiogenic phenotype is another feature of high-grade cervical intraepithelial neoplasia (CIN). However, their associations with the progression of low-grade CIN to high-grade CIN are unexplored. We investigated whether these proteolytic enzyme expressions correlate with the progression of CIN. A total of 39 paraffin-embedded specimens from 10 patients with CIN grade 1, nine with CIN grade 2, and 20 with CIN grade 3 were assessed immunohistochemically by specific antibodies against MMP-2, MMP-9, and uPA. MMP-9 expression was higher in CIN 3 lesions (47.4%) than in CIN 1 (22.2%) and CIN 2 (20.2%) lesions, although the difference failed to reach statistical significance. The expression level of uPA and MMP-2 was not associated with the grade of CIN lesions. Interestingly, we found a significant association between expressions of uPA and MMP-2 (P= 0.028). Our results suggest that MMP-9 might play a role in the progression of CIN.

Expression of vascular endothelial growth factor and hypoxia inducible factor-1alpha in cervical neoplasia.

Altered angiogenesis is an important phenotype of high-grade cervical lesions and invasive cervical carcinomas. Many researchers, including us, have shown that oncoproteins of human papillomavirus could enhance the vascular endothelial growth factor (VEGF) expression. We investigated the change in VEGF and hypoxia-inducible factor-1alpha (HIF-1alpha) expression patterns that occur during the carcinogenesis and progression of cervical cancer. Expressions of HIF-1alpha and VEGF were evaluated by immunohistochemistry using paraffin-embedded specimens obtained from 41 patients with a normal cervix, 39 patients with cervical intraepithelial neoplasia (CIN 1, 10; CIN 2/3, 29), and 36 patients with cervical cancer. The VEGF and HIF-1alpha expressions were higher in CIN and invasive cancer than in normal cervix (P= 0.021, P < 0.001, respectively). It is interesting to note that there was no significant difference in VEGF and HIF-1alpha overexpressions between CIN 2/3 and cervical cancer and between nonmetastatic and metastatic cancers. In addition, there was a significant correlation between the immunohistochemical score of HIF-1alpha and that of VEGF expression (Spearman's correlation coefficient 0.275, P= 0.003, n= 116). Taken together, the results of our study suggest that expressions of VEGF and HIF-1alpha could be involved in cervical carcinogenesis. In addition, the weak correlation between VEGF and HIF-1alpha expressions suggests that regulatory mechanisms other than HIF-1alpha may be involved in the expression of VEGF during cervical carcinogenesis.

Effect of epidermal growth factor receptor inhibitor alone and in combination with cisplatin on growth of vulvar cancer cells.

A recent study reported on the efficacy of the EGFR inhibitor on locally advanced vulvar cancer. The aim of this study was to evaluate the effect of an EGFR tyrosine kinase inhibitor (AG1478) alone and in combination with cisplatin on vulvar cancer cells (A431 and SW962). We detected overexpression of EGFR in A431 cells and low expression in SW962 cells. We found that the growth inhibitory effect of AG1478 was dependent upon the expression level of EGFR. The combined treatment of AG1478 with cisplatin failed to exert any synergistic or additive effect in either cell line. In the EGFR signaling pathway, AG1478 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) in parallel with decreased activity of EGFR in A431 cells, while no changes in ERK and Akt were observed in SW962 cells. The combination of AG1478 with cisplatin completely inhibited the phosphorylation of ERK and Akt in A431 cells but not in SW962 cells. Cisplatin alone and its combination with AG1478 increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) in both cell lines. In summary, AG1478 inhibited the growth activity of vulvar cancer cells, depending upon the expression level of EGFR, by inhibiting the activities of EGFR, Akt, and ERK. Given the absence of synergistic effects from the combination of AG1478 with cisplatin, combination therapy should be considered cautiously.

Efficacy and outcome of anterior vaginal wall repair using polypropylene mesh (Gynemesh).

AIM: The aim of the present study was to assess the safety and efficacy of anterior vaginal wall repair using polypropylene mesh for the correction of anterior vaginal wall prolapse. METHODS: From May 2001 to March 2005, 38 patients with cystoceles or uterine prolapse underwent transvaginal repair with implantation of polypropylene mesh. In all 38 patients anterior vaginal wall repair was done concurrently with other procedures: vaginal hysterectomy, n = 18 (47.4%) and tension-free vaginal tapes n = 22 (57.9%). RESULTS: Preoperatively 26 patients (68.4%) had stage III/IV prolapse on pelvic organ prolapse quantification examination. After mean follow up of 23.4 months, the objective cure rate at 12 and 18 months was 94.5% and 94.3%, respectively. As for complications associated with placement of the polypropylene mesh, no tissue erosion or infection was found. CONCLUSIONS: Transvaginal implantation of polypropylene mesh is an effective and safe technique for the correction of anterior vaginal wall prolapse.

Increasing trend in the incidence of cervical cancer among the elderly in Korea: a population-based study from 1993 to 2002.

Cancer is primarily a disease of older adults. However, little data is available on the clinical features of cervical cancer in elderly patients. We investigated the trends in incidence and clinical features associated with cervical cancer among the elderly in Korea during the period of 1993-2002. We obtained data from the National Cervical Cancer Incidence Database, which was constructed in collaboration with the Korea Central Cancer Registry (KCCR) and Korea Gynecologic Cancer Registry (KGCR). A total of 44 191 women with cervical cancer were diagnosed between 1993 and 2002. Patients were divided into three groups based on age: /=70 years (Group 3). During this period, upward incidence trends were noted in Group 3 while constant and downward incidence trends were noted in Groups 1 and 2, respectively. Pooled analysis across years revealed that squamous cell carcinoma and advanced stage (IIB, III, and IV) were more common in Group 3 than in Groups 1 and 2. With regard to primary treatments in the elderly patients, surgery appeared to be performed increasingly despite the fact that advanced stage (IIB, III, and IV) was more common in Group 3 than in Groups 1 and 2. Our findings suggest that the incidence of cervical cancer in the elderly is increasing in Korea, while it is decreasing overall. The current health service must emphasize education for the elderly about cervical cancer prevention while concentrating on screening.

Hypermethylation of the COX-2 gene is a potential prognostic marker for cervical cancer.

AIM: The aim of the present study was to evaluate the DNA hypermethylation profiles of 14 genes known to be associated with tumor behavior and their clinical significance in cervical cancer. METHOD: The clinical features of 82 patients with stage IB cervical cancer were analyzed in terms of DNA hypermethylation of 14 genes (hMLH1, p16, COX-2, CDH1, APC, DAPK, MGMT, p14, RASSF1A, RUNX3, TIMP3, FHIT, THBS1, and HLTF). RESULTS: Of 14 genes investigated, only hypermethylation of COX-2 showed significant association with poor disease-free survival (P = 0.001). To further investigate an alteration in COX-2 expression by DNA hypermethylation, immunohistochemistry for COX-2 protein was performed in the cervical cancer tissues. We found no significant association between hypermethylation and expression patterns of the COX-2 gene. CONCLUSIONS: The present results suggest that DNA hypermethylation of the COX-2 gene may be a potential prognostic marker in early stage cervical cancer, the underlying mechanism of which is independent of gene silencing.

The C19007T polymorphism of ERCC1 and its correlation with the risk of epithelial ovarian and endometrial cancer in Korean women. A case control study.

BACKGROUND: Excision repair cross-complementing group 1 (ERCC1) is a major DNA repair protein. Recent studies have addressed the association between ERCC1 polymorphism and carcinogenesis. METHODS: We investigated a polymorphism of ERCC1 at nucleotide 19007 (C-->T, Asn118Asn) in 94 epithelial ovarian cancer patients, 102 endometrial cancer patients, and in 329 control subjects. RESULTS: We observed no evidence of associations between the C19007T ERCC1 polymorphism and risk of epithelial ovarian or endometrial cancer, which had the same adjusted odds ratios of 0.91 (p = 0.711, 0.691 respectively). CONCLUSION: Our findings suggest that the C19007T ERCC1 polymorphism is unlikely to play an important role in epithelial ovarian or endometrial cancer in Korean women.

Clinical impact of integrated PET/CT on the management of suspected cervical cancer recurrence.

OBJECTIVES: To assess the value and clinical impact of integrated PET/CT using (18)F-FDG in the diagnosis and management of women with suspected cervical cancer recurrence. METHODS: Fifty-two patients with cervical cancer with suspected recurrence because of clinical, cytological, biochemical and radiological findings were retrospectively evaluated. A final diagnosis of recurrence was confirmed by histologic tissue biopsy or by further clinical or radiological evidence. The clinical impact of information provided by PET/CT on patient management was assessed on the basis of clinical follow-up data concerning further diagnostic or therapeutic approach. RESULTS: Twenty-eight of 32 positive PET/CT scans (87.5%) were proven to have recurrent disease. Seventeen of 20 negative PET/CT scans (85.0%) had no evidence of disease. The sensitivity, specificity, and accuracy of PET/CT for detecting recurrence were 90.3%, 81.0%, and 86.5% respectively. PET/CT changed the management of 12 patients (23.1%) by changing treatment plan (5 patients), by initiating unplanned treatment strategy (4 patients), or by obviating the need for planned diagnostic procedures (3 patients). Median duration after performing PET/CT and last follow-up was 12 (range: 6-27) months, and the 2-year disease-free survival rate of patients with negative PET/CT scan for recurrence was significantly better than that of patients with positive PET/CT (85.0% vs. 10.9%, P=0002). CONCLUSIONS: In patients with a suspected recurrence of cervical cancer, integrated PET/CT using (18)F-FDG provides good anatomic and functional localization of suspicious lesions, and the better diagnostic interpretation has an impact not only on clinical management and treatment planning of patients, but also on disease-free survival.

Association of promoter hypermethylation of the RASSF1A gene with prognostic parameters in endometrial cancer.

RASSF1A is a tumor suppressor gene that is frequently hypermethylated in various human cancers. In the present study, we examined RASSF1A methylation status in 70 patients with endometrial cancer to search for correlations between the promoter hypermethylation of RASSF1A and the clinicopathologic parameters. Thirty-six of 70 endometrial cancers demonstrated hypermethylation of the RASSF1A promoter. Advanced stage disease (FIGO stage III, IV), lymph node involvement, and high grade (G3) are more frequent in patients with RASSF1A hypermethylation than in those without. We also observed a higher incidence of recurrences and lower disease-free survival (DFS) in patients with RASSF1A hypermethylation (77.8% and 97.0% at 5 years for methylated and unmethylated patients, respectively, p = 0.039). Our results suggest that RASSF1A hypermethylation might be a useful indicator of tumor aggressiveness in endometrial cancer patients.