Špela Smrkolj

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 womens age at operation, type of operation, cell type, mitotic activity, invasive growth pattern, host defense reaction, lymph-vascular space invasion and patients survival. Additionally, using the Rainers scoring system, the prognostic score for each MIC was calculated. RESULTS The mean womens 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 mm(2). In 66 (74.2%) women the suggested treatment was conization, according to the Rainers 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.

STAR and AKR1B10 are down-regulated in high-grade endometrial cancer

Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential of STAR and AKR1B10 as prognostic biomarkers, which calls for further validation at the protein level.

Clinicopathological characteristics of cervical cancer between 2003 and 2005, after the introduction of a national cancer screening program in Slovenia

OBJECTIVE An organized cervical cancer (CC) screening program was introduced in Slovenia in 2003. With the purpose of clinical audit we analyzed the clinicopathological characteristics of CC patients for the period between 2003 and 2005. STUDY DESIGN The retrospectively collected data of 450 CC patients were presented at three Advisory Boards of Gynecologic Oncology in Slovenia. They were stratified for stage, tumor characteristics and treatment methods according to gynecologic examination attendance in the last 5 years preceding the diagnosis of CC (attenders vs. nonattenders). RESULTS In the period of observation, 242 women (53.8%) visited their gynecologists in the 5-year period prior to diagnosis of CC. Squamous cell carcinoma was present in 378 women (84.0%), adenocarcinoma in 45 (10.0%), adenosquamous carcinoma in 24 (5.3%) and other types in 3 women (0.7%). Attenders were significantly more frequently diagnosed with squamous cell carcinoma than nonattenders (chi-square=5.13; P<0.05). Attenders were significantly more frequently diagnosed in stage IA than in stage IB (chi-square=22.35; P<0.01). Similarly, in attenders stage I was significantly more frequent than stage II (chi-square=18.81; P<0.01). Pathologic smears of women with CC in the last 5-year period were most frequently evaluated as Pap II in the years 2003 and 2004 (in 39.1 and 26.4% of women, respectively) and as Pap III (in 27.9% of women) in 2005. Surgery was performed in 282 women (62.7%), radiotherapy in 158 (35.1%), symptomatic therapy in 9 (2.0%) and chemotherapy alone in 1 (0.2%) woman. In attenders, surgery alone was the most frequent treatment method (chi-square=91.18; P<0.01). CONCLUSION Only in attenders a significant redistribution of CC stages in favor of early stages is observed, and in these women more conservative and less extensive treatment methods could be applied.

Cancer Stem Cell–Related Marker NANOG Expression in Ovarian Serous Tumors: A Clinicopathological Study of 159 Cases

Objective The objectives of this study were to assess cancer stem cell–related marker NANOG expression in ovarian serous tumors and to evaluate its prognostic significance in relation to ovarian serous carcinoma. Methods NANOG protein expression was immunohistochemically evaluated in the ovarian tissue microarrays of 20 patients with benign ovarian serous tumors, 30 patients with borderline ovarian serous tumors, and 109 patients with ovarian serous carcinomas, from which 106 were of high-grade and 3 of low-grade morphology Immunohistochemical reaction was scored according to signal intensity and the percentage of positive cells in tumor samples. Pursuant to our summation of signal intensity and positive cell occurrence, we divided our samples into 4 groups: NANOG-negative, NANOG–slightly positive, NANOG–moderately positive, and NANOG–strongly positive group. Complete clinical data were obtained for the ovarian serous carcinoma group, and correlation between clinical data and NANOG expression was analyzed. Results A specific brown nuclear, or cytoplasmic reaction, was considered a positive NANOG staining. In terms of the ovarian serous carcinoma group, 69.7% were NANOG positive, 22.9% slightly positive, 22.9% moderately positive, and 23.9% strongly positive. All NANOG-positive cases were of high-grade morphology. Benign and borderline tumors and low-grade serous carcinomas were NANOG negative. There was no significant correlation between NANOG expression and clinical parameters in terms of the ovarian serous carcinoma group. Conclusions Positive NANOG expression is significantly associated with high-grade ovarian serous carcinoma and is absent in benign, borderline, and low-grade serous lesions. In our study, there was no correlation between NANOG expression and clinical parameters, including its use in the prognosis of ovarian serous carcinoma.

Novel algorithm including CA-125, HE4 and body mass index in the diagnosis of endometrial cancer

OBJECTIVES To evaluate the diagnostic and prognostic potential of preoperative serum CA-125 and HE4 levels in patients with endometrial cancer. METHODS Prospective case-control study of 133 women who underwent surgical treatment at the University Medical Centre Ljubljana (64 patients with endometrial cancer, 69 control patients with prolapsed uterus or myoma). Serum CA-125 and HE4 levels were determined using electrochemiluminescent assays. RESULTS Serum CA-125 and HE4 levels were significantly higher in patients with endometrial cancer, compared to the controls (p=2.67×10-4, 1.36×10-7, respectively). A diagnostic model that combines serum CA-125 and HE4 levels and body mass index separated patients with endometrial cancer from controls, with AUC of 0.804, sensitivity of 66.7%, and specificity of 84.6%. Serum HE4 levels showed good prognostic potential and stratified the patients according to presence/absence of deep myometrial invasion (p=0.001) or lymphovascular invasion (p=0.003), with AUCs of 0.78 and 0.81, respectively. In low-risk patients with grade 1 and 2 endometrioid cancer for whom lymphadenectomy can be avoided, HE4 allowed stratification according to deep myometrial invasion (p=3.39×10-4), with AUC of 0.84. Although median HE4 levels were higher in patients with lymphovascular invasion, this difference did not reach significance (p=0.06). CONCLUSIONS A model based on preoperative serum CA-125 and HE4 levels and body mass index has good diagnostic accuracy for separation of patients with endometrial cancer and control patients. In patients with endometrial cancer, serum HE4 levels allow prediction of deep myometrial and lymphovascular invasion.

Data on expression of genes involved in estrogen and progesterone action, inflammation and differentiation according to demographic, histopathological and clinical characteristics of endometrial cancer patients

Endometrial cancer is the sixth most common cancer in women worldwide. It is associated with aberrant actions of steroid hormones, estrogens and progesterone, but also with enhanced inflammation and reduced cellular differentiation. Here, we show data on demographic and histopathological characteristics of 51 patients with endometrial cancer, together with data on correlations between the expression of 38 genes involved in estrogen and progesterone actions, inflammation and differentiation, and demographic characteristics. We also show data on changes in gene expression of these 38 genes according to histopathological and clinical characteristics of these patients. This article includes data referenced in the manuscript entitled »STAR and AKR1B10 are down-regulated in high-grade endometrial cancer by Sinreih et al. (in press) [1].

Models including plasma levels of sphingomyelins and phosphatidylcholines as diagnostic and prognostic biomarkers of endometrial cancer

In endometrial cancer, biomarkers for preoperative identification of patients with low risk for disease progression would enable stratification according to the extent of surgery needed, and would avoid the complications that can be associated with radical surgery. A panel of proteins, amino acids, enzymes, and miRNA has been investigated as potential biomarkers for endometrial cancer. At the time of the manuscript submission targeted metabolomics/lipidomics approaches have not been applied to biomarker research in endometrial cancer. Using electrospray ionization-tandem mass spectrometry we quantified 163 metabolites in 126 plasma samples (61 patients with endometrial cancer, 65 control patients). Three single phosphatidylcholines were identified with significantly decreased levels in patients with endometrial cancer. A diagnostic model was defined as the ratio between acylcarnitine C16 and phosphatidylcholine PCae C40:1, the ratio between proline and tyrosine, and the ratio between the two phosphatidylcholines PCaa C42:0 and PCae C44:5; which provided sensitivity of 85.25%, specificity of 69.23%, and AUC of 0.837. Addition of smoking status further improved the constructed diagnostic model (AUC = 0.855). The presence of the major prognostic factors of deep myometrial invasion and lymphovascular invasion were also associated with altered metabolite concentrations. A prognostic model for deep myometrial invasion included the ratio between two hydroxysphingomyelins SMOH C14:1 and SMOH C24:1, and the ratio between two phosphatidylcholines PCaa C40:2 and PCaa C42:6, which provided sensitivity of 81.25%, specificity of 86.36%, and AUC of 0.857. The model for lymphovascular invasion included the ratio between two phosphatidylcholines PCaa C34:4 and PCae C38:3, and the ratio between acylcarnitine C16:2 and phosphatidylcholine PCaa C38:1, which provided sensitivity of 88.89%, specificity of 84.31%, and AUC of 0.935.

Evaluation of prognostic factors for advanced ovarian cancer treatment with an emphasis on optimal primary cytoreduction

Background: Initial surgical debulking followed by a systemic chemotherapy is the standard treatment sequence for advanced ovarian cancer (AOC) treatment. The purpose of this article is to evaluate prognostic factors that impact the success of AOC treatment. Methods: All patients with AOC (FIGO stage III and IV) who were surgically treated at the Division of Gynaecology, University Medical Centre of Ljubljana, in the period from 2003 to 2008 and further received cytotoxic chemotherapy at the Institute of Oncology in Ljubljana were included in this retrospective study. Women with advanced borderline ovarian cancer and patients who initially received neoadjuvant chemotherapy and those whose adjuvant chemotherapy was not platinum-based were excluded from the analysis. Results: A total of 159 women were enrolled in the study, while data were analyzed for 116 patients. Their median age was 59 years (23–80 years) and did not have a significant influence on the treatment outcome. Clear-cell histological type of AOC was an important risk factor for a disease-free interval (DFI) (HR = 2.41, CI 95 % 0.9–5.9; p = 0.08) and overall survival (OS) (HR 4.045; 95.0 % CI 1.5–10.6; p = 0.003). Postoperative residual tumour larger than 2 cm represented a statistically independent risk factor for poor OS. Residual tumour in the upper abdomen did not represent a statistically significant risk factor either for DFI (HR = 1.93; CI 95 % 0.9–4.06; p = 0.08) or for OS (HR = 1.47; 95.0 % CI 0.5–3.8; p = 0.491). Median follow up time was 29.5 months, median DFI 18 months (95 % CI 16– 20) and median OS 32 months (95 % CI 22–42). 74 (63.8 %) patients died. Conclusion: Clear-cell histological type of AOC and residual tumour larger than 2 cm are the most important risk factors for early progress of the disease and poor OS. Hence improvement of surgical treatment is crucial for better treatment outcomes for patients with AOC. The latter can be achieved by an interdisciplinary surgical approach.