Evaluation of Clinical and Pathologic Risk Factors May Reduce the Rate of Multimodality Treatment of Early Cervical Cancer.

OBJECTIVE: To assess the rate of postoperative adjuvant treatment in patients who underwent radical hysterectomy for early cervical cancer and to suggest criteria for the triage of patients who have a high probability of multimodality treatment. METHODS: This was a multicenter retrospective study of 514 patients with FIGO stages IA2-IIA cervical cancer who underwent radical hysterectomy between 1999 and 2010. The patients were divided into 2 groups according to whether or not postoperative radiation was administered. The 2 groups were compared with regard to clinical and histopathologic variables divided into major and minor criteria (intermediate risk factors) based on lymph nodes status, parametrial involvement, tumor size, deep stromal invasion, and lymph-vascular space invasion. RESULTS: We identified 294 (57.2%) patients who received adjuvant postoperative radiotherapy (RT) or chemoradiation. Fifty-three percent of these patients who were treated by adjuvant radiation had only intermediate risk factors. Combining the various combinations of 2 out of 3 of the following criteria, we found that 89% of patients with tumors ≥2 cm and lymph-vascular space invasion received RT, 76% of patients with tumors ≥2 cm and depth of invasion >10 mm received RT, and 87% of patients with tumors depth of invasion >10 mm and lymph-vascular space invasion received RT. CONCLUSIONS: This study suggests that in patients with early cervical cancer, clinicopathologic evaluation of tumor size and lymph-vascular space invasion should be undertaken before performing radical hysterectomy. This approach can serve to tailor treatment, reducing the rate of employing both radical hysterectomy and chemoradiation.

[Treatment of advanced ovarian carcinoma: surgery before chemotherapy or chemotherapy before surgery?].

The standard of care for advanced epithelial ovarian carcinoma has been primary surgery aspiring for optimal debulking followed by adjuvant chemotherapy. A significant survival advantage has been demonstrated in women having optimal debulking at primary surgery compared to women having less than optimal debulking at primary surgery. With the advent of efficient chemotherapy for ovarian carcinoma (combination of platinum and taxan), the administration of several courses of chemotherapy before surgery (neoadjuvant chemotherapy) has been established as a method for reducing the intra-abdominal tumor burden and, thereby, increasing the probability of optimal debulking at surgery which is usually performed in the interval between course no. 3 and no. 4 of chemotherapy (interval surgery). Higher rates of optimal debulking, Lower rates of surgical complications, but no differences in survival, have been demonstrated in women having chemotherapy before surgery compared to women having surgery before chemotherapy. Obviously, the method of neoadjuvant chemotherapy is the treatment of choice for women in whom the clinical evaluation indicates that there is no high probability of optimal debulking at primary surgery. Nevertheless, there has been a debate on whether or not the method of neoadjuvant chemotherapy should also be applied for women in whom the clinical evaluation indicates that they are fit for optimal debulking at primary surgery. There is a need for more prospective studies to evaluate the role of neoadjuvant chemotherapy in the treatment of ovarian carcinoma.

Integration of PET/CT into the preoperative evaluation of patients with early cervical cancer does not decrease the proportion of patients with positive lymph nodes found after surgery.

PURPOSE: The aim of this study was to evaluate whether preoperative positron emission tomography/computed tomography (PET/CT) in patients with early-stage cervical carcinoma reduced the proportion of patients with metastatic lymph nodes identified after surgery. PATIENTS AND METHODS: This is a multicenter case-control study of 599 patients with early cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy at 1 of 10 gynecological oncology units in Israel. The patients were divided into 2 groups according to whether or not they underwent a preoperative PET/CT. The primary outcome was the proportion of patients with nodal involvement. The 2 groups were compared with regard to the clinical and histological variables. RESULTS: Of the 599 patients who underwent surgery, 180 (36%) had preoperative PET/CT study. There were no significant differences between the PET/CT and control groups with regard to clinical and histological risk factors. The proportion of patients with involved nodes was similar in the control and PET/CT groups (20.8% vs 19%; P = 0.73) as well as the proportion of patients receiving adjuvant radiotherapy/chemoradiation (58.3% vs 55.1%; P = 0.55). CONCLUSIONS: Preoperative PET/CT in patients with early cervical cancer does not reduce proportion of patients with metastatic nodal involvement and the employment of multimodality treatment. Prospective clinical trials comparing management based on PET/CT findings are warranted.

Expression of IL-18, IL-18 binding protein, and IL-18 receptor by normal and cancerous human ovarian tissues: possible implication of IL-18 in the pathogenesis of ovarian carcinoma.

Proinflammatory cytokine IL-18 has been shown to be elevated in the sera of ovarian carcinoma patients. The aim of the study was to examine the levels and cellular origin of IL-18, IL-18 binding protein, and IL-18 receptor in normal and cancerous ovarian tissues. Ovarian tissue samples were examined by immunohistochemical staining for IL-18, IL-18BP, and IL-18R and mRNA of these cytokines was analyzed with semiquantitative PT-PCR. IL-18 levels were significantly higher in cancerous ovarian tissues (P = 0.0007), IL-18BP levels were significantly higher in normal ovarian tissues (P = 0.04), and the ratio of IL-18/IL-18BP was significantly higher in cancerous ovarian tissues (P = 0.036). Cancerous ovarian tissues expressed significantly higher IL-18 mRNA levels (P = 0.025), while there was no difference in the expression of IL-18BP mRNA and IL-18R mRNA between cancerous and normal ovarian tissues. IL-18 and IL-18BP were expressed dominantly in the epithelial cells of both cancerous and normal ovarian tissues, while IL-18R was expressed dominantly in the epithelial cells of cancerous ovarian tissues but expressed similarly in the epithelial and stromal cells of normal cancerous tissues. This study indicates a possible role of IL-18, IL-18BP, and IL-18R in the pathogenesis of epithelial ovarian carcinoma.

Distinct expression and localization of TNF system in ovarian carcinoma tissues: possible involvement of TNF-α in morphological changes of ovarian cancerous cells.

BACKGROUND/AIM: It has been previously shown that epithelial ovarian carcinoma tissues express high levels of tumor necrosis alpha (TNF-α), interleukin (IL)-6, IL-1α and IL-1ß. The aim of the present study was to evaluate the localization of TNF-α and its receptors (TNFR1 and TNFR2) in different types of ovarian carcinoma tissues and the possible role of TNF in the pathogenesis of epithelial ovarian carcinoma. MATERIALS AND METHODS: Total RNA was extracted from normal and cancerous ovarian tissues and mRNA was analyzed with semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Immunohistochemical staining was performed with use of antibodies against human (ah)TNFR1 and TNF2. RESULTS: TNF-α mRNA and TNFR2 mRNA levels were significantly higher in ovarian carcinoma tissues than in normal ovarian tissues, whereas TNFR1 mRNA levels were similar. TNFR1 and TNFR2 were mainly localized in the epithelial neoplastic cells of the tumor. Knocking-down TNF-α activity with αhTNF-a altered ovarian carcinoma cell morphology (with more branches) in vitro. CONCLUSION: Our study indicates a possible role of TNF-α in epithelial ovarian carcinoma pathogenesis through TNFR2, which affects morphological changes, which may be involved ovarian cancer pathogenesis.

An Antibody-based Blood Test Utilizing a Panel of Biomarkers as a New Method for Improved Breast Cancer Diagnosis.

In order to develop a new tool for diagnosis of breast cancer based on autoantibodies against a panel of biomarkers, a clinical trial including blood samples from 507 subjects was conducted. All subjects showed a breast abnormality on exam or breast imaging and final biopsy pathology of either breast cancer patients or healthy controls. Using an enzyme-linked immunosorbent assay, the samples were tested for autoantibodies against a predetermined number of biomarkers in various models that were used to determine a diagnosis, which was compared to the clinical status. Our new assay achieved a sensitivity of 95.2% [CI = 92.8-96.8%] at a fixed specificity of 49.5%. Receiver-operator characteristic curve analysis showed an area under the curve of 80.1% [CI = 72.6-87.6%]. These results suggest that a blood test which is based on models comprising several autoantibodies to specific biomarkers may be a new and novel tool for improving the diagnostic evaluation of breast cancer.

Thalidomide distinctly affected TNF-α, IL-6 and MMP secretion by an ovarian cancer cell line (SKOV-3) and primary ovarian cancer cells.

BACKGROUND: Thalidomide inhibits TNF-α production in lipopolysaccharide-stimulated monocytes. The aim of this study was to evaluate the effect of thalidomide on TNF-α, IL-6 and MMP secretion in epithelial ovarian carcinoma cells. MATERIALS AND METHODS: SKOV-3 cells and primary epithelial ovarian carcinoma cells were cultured in the presence of various concentrations of thalidomide. Cell proliferation was examined by MTT proliferation assay. TNF-α and IL-6 levels were determined in the supernatants of the cell cultures by ELISA, and MMP activity was examined by gelatin zymography. RESULTS: Thalidomide did not significantly affect the proliferation and growth of SKOV-3 cells. However, it decreased significantly the capacity of SKOV-3 cells and primary epithelial ovarian carcinoma cells to secrete TNF-α. Thalidomide also significantly decreased the capacity of SKOV-3 cells, but not primary epithelial ovarian carcinoma cells, to secrete MMP-9 and MMP-2. However, thalidomide did not affect IL-6 secretion in SKOV-3 cells or primary epithelial ovarian carcinoma cells. CONCLUSION: Our study suggests that thalidomide distinctly affected TNF-α, IL-6 and MMPs secretion by an ovarian carcinoma cell line (SKOV-3) and primary ovarian cancer cells. This might suggest a different susceptibility of these two types of cells to thalidomide, and/or that the mechanisms of secretion of the factors examined are differently regulated in these cells. Our results may deepen our understanding the mechanism/s of action of thalidomide in ovarian carcinoma cells. The results might have important implications in future therapeutic strategies that will incorporate thalidomide and other cytokine inhibitors in the treatment of epithelial ovarian carcinoma.

The influence of early diagnosis of endometrioid endometrial cancer on disease stage and survival.

OBJECTIVE: To evaluate whether the presence or duration of uterine bleeding is associated with disease stage, and survival of patients with endometrioid endometrial carcinoma (EEC). METHODS: The records of 220 patients with EEC who underwent surgery were reviewed. The patients were divided into three groups according to the presence and duration of vaginal bleeding at the time of surgery. Group 1, without vaginal bleeding; group 2, vaginal bleeding up to 3 months; group 3, vaginal bleeding exceeding 3 months prior to surgery. Disease stage and survival were between the three groups. RESULTS: Of the 220 patients, 42 (19%) were asymptomatic; 95 (43%) had symptom duration of up to 3 months and 83 (38%) experienced bleeding for >3 months. There were no significant differences between groups 1, 2 and 3 regarding the proportion of patients with deep invasion in stage I (21, 24, 26%, p = 0.84; respectively), with grade 3 tumors (10, 13, 14%, p = 0.42; respectively) or with advanced stage disease (12, 14, 15%, p = 0.92; respectively). Survival analysis demonstrated a non-significant trend toward better survival in asymptomatic patients and in patients with a shorter duration of symptoms (p = 0.172). CONCLUSIONS: Diagnosis of EEC in asymptomatic patients or in patients with a short duration of bleeding is associated with comparable stage and survival.

Brain metastases from endometrial carcinoma.

This paper will focus on knowledge related to brain metastases from endometrial carcinoma. To date, 115 cases were documented in the literature with an incidence of 0.6% among endometrial carcinoma patients. The endometrial carcinoma was usually an advanced-stage and high-grade tumor. In most patients (~90%), brain metastasis was detected after diagnosis of endometrial carcinoma with a median interval from diagnosis of endometrial carcinoma to diagnosis of brain metastases of 17 months. Brain metastasis from endometrial carcinoma was either an isolated disease limited to the brain only (~50%) or part of a disseminated disease involving also other parts of the body (~50%). Most often, brain metastasis from endometrial carcinoma affected the cerebrum (~75%) and was solitary (~60%). The median survival after diagnosis of brain metastases from endometrial carcinoma was 5 months; however, a significantly better survival was achieved with multimodal therapy including surgical resection or stereotactic radiosurgery followed by whole brain radiotherapy (WBRT) and/or chemotherapy compared to WBRT alone. It is suggested that brain imaging studies should be considered in the routine follow up of patients with endometrial carcinoma and that the search for a primary source in females with brain metastases of unknown primary should include endometrial biopsy.

Brain metastases from ovarian carcinoma.

This paper will focus on knowledge related to brain metastases from ovarian carcinoma. So far, less than 600 cases were documented in the literature with an incidence among ovarian carcinoma patients ranging from 0.29% to 11.6%. The ovarian carcinoma was usually an advanced-stage epithelial serous carcinoma, and the median interval between diagnosis of ovarian carcinoma and brain metastases was 2 years. Most often, brain metastases, affected the cerebrum, were multiple and part of a disseminated disease. Treatment of brain metastasis has evolved over the years from whole brain radiotherapy (WBRT) only to multimodal therapy including surgical resection or stereotactic radiosurgery followed by WBRT and/or chemotherapy. The median survival after diagnosis of brain metastases was 6 months; nevertheless, a significantly better survival was achieved with multimodal therapy compared to WBRT only. It is suggested that brain imaging studies should be included in the followup of patients after treatment for ovarian carcinoma.

Autoantibodies to tailor-made panels of tumor-associated antigens in breast carcinoma.

Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identified in the sera of cancer patients. In a previous review published in this journal, we have focused on recent knowledge related to circulating AAbs to individual TAAs in breast carcinoma. This review will focus on recent knowledge related to AAb assays to tailor-made panels of TAAs in breast carcinoma. So far, AAb assays to the following tailor-made panels of TAAs have been assessed in breast carcinoma: (1) p53, c-myc, HER2, NY-ESO-1, BRCA2, and MUC1, (2) IMP1, p62, Koc, p53, c-MYC, cyclin B1, and survivin, (3) PPIA, PRDX2, FKBP52, HSP-60, and MUC1, (4) MUC1, HER2, p53, and IGFBP2, (5) p53, HER2, IGFBP-2, and TOPO2α, (6) survivin and livin, (7) ASB-9, SERAC1, and RELT, and (8) p16, p53, and c-myc. Assessment of serum AAbs to a tailor-made panel of TAAs provides better sensitivity to diagnosis of breast carcinoma than measuring serum AAbs to a single TAA. Nevertheless, measurement of serum AAbs to a panel of TAAs for screening and early diagnosis of breast carcinoma is still investigational and should be carried out along with traditional diagnostic studies.

Obstetric outcome following cervical conization.

OBJECTIVE: The purpose of the present study was to examine obstetric outcome of patients following conization and specifically the risk for preterm delivery (PTD). METHODS: A population-based study was performed comparing pregnancies in women following conization with those who had not undergone the procedure. Stratified analysis, using a multiple logistic regression model was performed to control for confounders. RESULTS: Out of 104,670 deliveries, 53 women (0.05%) had undergone conization. Most conizations were performed using loop electrosurgical excision procedure (LEEP). Using multivariable analysis, the following conditions were significantly associated with conization: advanced maternal age, PTD before the 34th week, low birth weight, and cervical incompetence with cerclage. Higher rates of perinatal mortality were noted in pregnancies of women with conization, but after controlling for PTD, the association lost its significance. The risk of PTD <34 weeks was significantly higher than the comparison group (OR 7.73 95% CI 3.77-15.85, p < 0.001). This association remained significant after controlling for confounders, such as cervical incompetence, smoking, maternal age, birth order and year of delivery (OR 2.8 95% CI 1.3-6.1, p = 0.008). When comparing pregnancy outcomes of women with and without cerclage due to cervical incompetence, no significant differences were documented. CONCLUSIONS: A clear association exists between conization and PTD before the 34th week. This association persists after controlling for variables considered to coexist with PTD. Careful surveillance is required in pregnancies of women following conization for early detection of preterm contractions and PTD.

Autoantibodies to tumor-associated antigens in breast carcinoma.

Autoantibodies (AAbs) to tumor-associated antigens (TAAs) have been identified in the circulation of patients with cancer. This paper will focus on recent knowledge related to circulating AAbs to TAAs in breast carcinoma. So far, the following TAAs have been identified to elicit circulating AAbs in breast carcinoma: p53, MUC-1, heat shock proteins (HSP-27, HSP-60, and HSP-90), HER2/neu/c-erb B2, GIPC-1, c-myc, c-myb, cancer-testis antigens (NY-ESO-1), BRCA1, BRCA2, endostatin, lipophilin B, cyclin B1, cyclin D1, fibulin, insulin-like growth factor binding protein 2 (IGFBP-2), topoisomerase II alpha (TOPO2α), and cathepsin D. Measurement of serum AAbs to one specific TAA only is of little value for screening and early diagnosis of breast carcinoma; however, assessment of AAbs to a panel of TAAs may have promising diagnostic potential.

[Splenic metastases from female genital tract malignancies].

Splenic metastases are rare. Usually, they are part of a disseminated disease and located on the splenic capsule. Common sources are breast cancer, lung cancer and malignant melanoma. SoLitary splenic metastases are rare, usuaLLy located in the splenic parenchyma and metastasizing via the hematogenous route. Splenic metastases from ovarian carcinoma are usuaLly part of a disseminated disease, located on the splenic capsule and metastasize via the peritoneum. Splenic metastases from endometriaL carcinoma are usuaLLy solitary, Located in the splenic parenchyma and metastasize via the hematogenous route. Splenic metastases from cervical carcinoma are divided equally between metastases as part of a disseminated disease and soLitary metastases. Less than 100 cases of solitary splenic metastases have been reported with half of them being metastases from female genital tract malignancies: 30--ovarian carcinoma; 11--endometriaL carcinoma; 8--cervical carcinoma; and 1--tubal carcinoma. Few cases have been reported of splenic rupture because of metastases from choriocarcinoma. Splenic metastases as part of a disseminated disease are associated with poor prognosis, and splenectomy--apart from cases in which it might assist in achieving optimaL debulking--is not effective. Solitary splenic metastases represent a more moderate disease and the treatment of choice is splenectomy. SoLitary splenic metastases may be detected after an interval from the diagnosis of the primary disease. Hence, patients who had been treated for female genital tract malignancy, even if they are asymptomatic, need a long-term follow-up, including serial imaging studies of the spleen.

The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients.

OBJECTIVES: The genes associated with familial Endometrial Cancer (EC) are largely unknown. While EC is an integral part of Hereditary Non-Polyposis Colon Cancer, there is an ongoing debate if EC is indeed overrepresented in hereditary breast/ovarian cancer families. METHODS: Unselected Jewish women with EC who were diagnosed from January 1982 to January 2008 were genotyped for the predominant mutations in Jewish individuals in BRCA1 (185delAG, 5382InsC, Tyr978X) BRCA2 (6174delT), MSH2 (A636P, 324delCA) and MSH6 (c.3984_3987dup). RESULTS: Overall, 289 Jewish women with EC were included, the majority (217-75%) were Ashkenazim. Mean age at diagnosis was 62.6 ± 12 years, the most common histopathology was type I (endometrioid carcinoma) (80.4% of participants) with 29 having type II (Uterine papillary serous and clear cell cancer) Most patients (85.4%) had stage 1 disease by the FIGO staging. Five women (1.7%-2.3% of the Ashkenazim) carried either the BRCA1*185delAG (n = 4) or BRCA2*6174delT (n = 1) mutations, a rate similar with that of the general Ashkenazi population. Notably, none of 34 women with type II EC carried any BRCA1/BRCA2 mutations. Four (1.8%) and three (1.4%) of the 217 Ashkenazim patients harbored the c.3984_3987dup, A636P, MSH6 and MSH2 mutations, respectively, and 1/72 (1.4%) of the non-Ashkenazi patients harbored the 324delCA MSH2 mutation. Three of 42 (7.1%) women with EC diagnosed < 50 years carried either BRCA1 MSH6 or MSH2 mutations. CONCLUSIONS: Our data do not support screening for BRCA1/2 mutations in consecutive EC patients.

Expression of IL-10 in human normal and cancerous ovarian tissues and cells.

IL-10 is an 18-kd polypeptide that has been shown to be secreted by multiple cell types, including T and B cells, monocytes and some human tumors. However, which cell population is responsible for the elevated IL-10 levels in the serum and ascites of ovarian cancer patients, whether ovarian carcinoma cells produce IL-10, and how IL-10 influences the development and progression of ovarian carcinoma are issues that remain unclear. The aim of our study was to examine IL-10 production and secretion by ovarian carcinoma tissues and cells, and to determine its possible role in the cell and tumor micro-environment. The mean IL-10 protein levels expressed in normal ovarian tissue homogenates were significantly higher compared to cancerous ovarian tissue (p = 0.002). Yet, the IL-10 mRNA expression was significantly higher in cancerous ovarian tissues as compared to normal tissues (p = 0.021). The IL-10 receptor mRNA expression levels of the cancerous ovarian tissue homogenates were slightly, but not significantly, higher than the normal tissues. IL-10 immunostaining revealed that in both normal and cancerous ovarian tissues, IL-10 expression could be detected mainly in epithelial cells. In normal ovarian tissues, similar levels of IL-10R were demonstrated in epithelial and stromal cells. However, in cancerous ovarian tissues, epithelial cells expressed higher levels of IL-10R than the stroma. Primary normal and cancerous ovarian cell cultures and SKOV-3 cells secreted similar amounts of IL-10 after 24 hours of incubation. Our results suggest that epithelial cells are the main source of IL-10 in the ovary. Nevertheless, the target cells for IL-10 are different in normal and cancerous ovarian cells. Thus, IL-10 and its receptor could be involved in the pathogenesis of ovarian carcinoma.

Three-dimensional power Doppler ultrasound in ovarian cancer and its correlation with histology.

PURPOSE: The aim of this study was to evaluate and quantify intraovarian blood flow with 3D power Doppler histogram analysis before surgical intervention in women suspected of having ovarian carcinoma and to determine the correlation with histology findings. METHODS: A prospective study was designed and 17 consecutive patients undergoing oophorectomy were included. Two groups of women were evaluated: high-risk women for ovarian pathologies and low-risk women with no known ovarian disease scheduled for bilateral oophorectomy for nonmalignant related pathology. Transvaginal ultrasound was performed using 2D, 3D-power Doppler ultrasound and histogram techniques. Four main parameters were evaluated: vascularization index (VI), flow index (FI), vascularization-flow index (VFI) and mean grayness (MG). Histological confirmation of the findings was done in all patients. Data were analyzed by the Mann-Whitney U test with P<0.05 considered as significant. RESULTS: Ultrasound scanning was performed for a total of 24 ovaries: 9 ovaries with cancer and 15 controls. There were no significant differences between the groups in all four histogram measurements: FI, VI, VFI and MG. There were no differences between the groups regarding ultrasound findings of free fluid in pelvis (16.7% in women with malignancy, 18.2% in women without ovarian malignancy; P=0.938) and the presence of complex ovarian cyst (83.8% in women with malignancy, 36.4% in women without ovarian malignancy; P=0.131). CONCLUSIONS: No significant differences were noted between benign and malignant ovaries in our population in all four indices of vascularity and perfusion of 3D power Doppler. Further large prospective studies should evaluate the significance of 3D power Doppler using histogram analysis in the early detection of ovarian cancer.

Evidence of measles virus antigens and RNA in endometrial cancer.

OBJECTIVES: To look for an association between the measles virus and endometrial carcinoma, the most frequent cancer of the female genital tract in our area. STUDY DESIGN: Thirty-six of 49 patients with endometrial carcinoma were studied to detect fingerprints of the measles virus. Immunohistochemistry with the avidin-biotin complex method and in situ hybridization were used to demonstrate the association. The clinicopathological correlations were carried out to support a relationship between the virus and the cancer if any was found. RESULTS: Twenty-six of the 36 cases (72%) of endometrial cancer showed the presence of measles virus antigens in the tumor cells. Sixteen of 21 cases were positive for measles virus RNA by in situ hybridization. Although type I endometrial carcinoma was more positive for viral particles than type II, type II cancer, when allied with the measles virus, was more often associated with the depth of myometrial invasion and with death from tumor. CONCLUSIONS: We demonstrate for the first time a link between endometrial cancer and the presence of viral antigens and RNA of the measles virus, although these findings do not necessarily signify a causal relationship between the cancer and the virus.