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Objectives: Chemotherapy-induced peripheral neuropathy (CIPN) is a common chemotherapy side effect, but its prevention and treatment remains a challenge. Neurotoxicity may lead to dose limitation or even treatment discontinuation, and therefore potentially affect the efficacy of anticancer treatment and long term outcomes. The practice to administer gabapentin for neuropathy may be applicable, but is limited by insufficient studies. The aim of our study was to assess the presence of chemotherapy-induced peripheral neuropathy in ovarian cancer patients treated with first-line paclitaxel and carboplatin chemotherapy and evaluate the effectiveness of gabapentin in treatment of this condition. Material and methods: 61 ovarian cancer patients treated with first line chemotherapy were included in the study. The first phase of the study was to assess neurological condition of each patient by: neuropathy symptoms scale, McGill’s scale, neurological deficit and quality of life, during the chemotherapy. In the second phase of the study we evaluated the response to gabapentin treatment in a group of patients who developed neuropathy. Results: 78.7% of the patients developed chemotherapy related neuropathy. During the course of chemotherapy these patients experienced significant exacerbation of neuropathy symptoms (p < 0.0001), neuropathic pain (p < 0.0001), neurologic deficit (p < 0.0012) and worsening of quality of life (p < 0.0002). Patients who were qualified to undergo the gabapentin treatment observed improvement in symptoms (p < 0.027), pain (p < 0.027) and neurologic deficit (p < 0.019). Quality of life did not change significantly after gabapentin treatment (p < 0.128). Conclusions: Chemotherapy substantially deteriorates the neurologic condition of the patients and the quality of life. Paclitaxel and carboplatin treated patients may benefit from gabapentin therapy in chemotherapy-induced peripheral neuropathy.

BACKGROUND/AIM It has been shown in many studies that expression of pyruvate kinase (PK) enzyme plays a key role during cellular metabolism. There is evidence that cancer cells manifesting very dynamic proliferation may control their division in various mechanisms, i.a. by expression of PKM2 isoform. The exact role of PKM2 in ovarian cancer (OC) cells and cancer associated fibroblasts (CAFs) have not been elucidated. MATERIALS AND METHODS The present study was focused on analysis of PKM2 expression in cancer cells and CAFs in 97 OC cases, mostly of serous histological type. Moreover, relationships between expression of PKM2 and proliferation (Ki-67; MCM-2, -3, -7; cyclin D1), vascular (CD31, D2-40) and mesenchymal (Vim and αSMA) markers as well as receptors (ER, PR, HER2, EGFR) were examined. All observations were evaluated in regard to available clinicopathological data. RESULTS The expression of PKM2 was disclosed only in cytoplasm of OC cells. No statistically significant correlation between PKM2 and tested markers was found. In regard to available clinicopathological data only an increasing trend of PKM2 expression with increasing grade of histological malignancy G was found (p=0.07). CONCLUSION Due to achieved results concerning expression of PKM2 there is a lack of evidence for its diagnostic and prognostic usage in OC.

Objectives: Since metformin was reported to decrease overall cancer incidence and mortality and to have antiproliferative and antiinvasive properties, we investigated the impact of metformin intake on survival in endometrial cancer patients. Material and methods: Medical records and survival data of 126 patients with endometrial cancer were analyzed retrospectively. U Mann-Whitney and chi-square tests were applied to compare clinicopathological features. Kaplan Meier model with log-rank test was used to compare survival in the subgroups. Cox proportional hazard model was applied to analyze the relationships between particular factors and overall survival. Results: 107 patients met study criteria and were divided into three groups: 1) patients with type 2 diabetes and metformin users (n=30), 2) patients with type 2 diabetes and metformin non-users (n=38), 3) patients without diabetes mellitus (n=39). No difference in survival between metformin users versus metformin non-users (p=0,86) was observed. Metformin intake, diabetes mellitus co morbidity, plasma glucose level and BMI appeared without influence on survival. When the analysis was restricted to the subgroup of type I endometrial cancer or to endometroid histological type, still neither metformin intake nor diabetes influenced the prognosis. Conclusions: Metformin intake does not alter overall survival in endometrial cancer patients. Diabetes mellitus has no influence on survival in endometrial cancer patients.

Vulvar melanoma is an aggressive neoplasm with a poor prognosis. Approximately 25% to 50% of patients survive 5 years [1]. This malignancy is prone to late metastasis, so 5-year survival does not equal cure. The management of recurrent disease continues to be experimental and individualized [2].

Objectives: The aim of this study was to assess the sensitivity and specificity of HE4 in detecting and differentiating between types I and II epithelial ovarian cancer (EOC) in comparison with CA125. Material and methods: We measured HE4 and CA125 serum concentrations in 206 samples taken from patients operated in Gynecologic Oncology Department due to ovarian tumors. Ovarian cancer was confirmed in 89 cases divided into type I and type II. 52 healthy patients without any gynecological disease formed the control group. The sensitivity and specificity for type I and type II EOC detection and differentiating between both types was evaluated for HE4 and CA125. Results: The HE4 and CA125 serum concentrations were significantly higher in type II than in type I EOC (p=0.008696, p=0.000243 respectively).The HE4 and CA125 sensitivity for type I and benign tumors differentiation was 63.16% for both of them and specificity was 87.29% vs 67.89% respectively. For CA125 these differences did not reach statistical significance. The HE4 sensitivity and specificity for type II and benign tumors differentiation were 87.14% and 96.61%, respectively, and for CA125 these values were 82.86% and 94.07%, respectively. Conclusions: Pretreatment analysis of HE4 serum concentration is superior to CA125 in differential diagnosis of ovarian cancer subtypes (I and II). HE4 is superior to CA125 in detecting ovarian cancer type II. Neither HE4 nor CA125 is an effective diagnostic tool for type I ovarian cancer detection. A new highly specific and highly sensitive tumor marker for type I EOC is needed.

Ovarian cancer (OC) is the leading cause of death among women with genital tract disorders. Melatonin exhibits oncostatic properties which it may effect through binding to its membrane receptor, MT1. The aim of this study was to determine the expression of MT1 in OC cells and to correlate this with clinical and pathological data. Immunohistochemistry was performed on 84 cases of OC. Normal ovarian epithelial (IOSE 364) and OC (SK-OV-3, OVCAR-3) cell lines were used to examine the MT1 expression at protein level using the western blot and immunofluorescence technique. The expression of MT1 was observed as cytoplasmic-membrane (MT1(CM)) and membrane (MT1(M)) reactions. A positive correlation between MT1(CM) and MT1(M) was found in all the studied cases. There were no significant differences between the expression of MT1(CM), MT1(M), and histological type, staging, grading, presence of residual disease, or overall survival time. Immunofluorescence showed both MT1(M) and MT1(CM) expression in all the tested cell lines. Western blot illustrated the highest protein level of MT1 in IOSE 364 and the lowest in the OVCAR-3. The results indicate the limited prognostic significance of MT1 in OC cells.

The incidence of endometrial cancer (EC) in the population of young women has been increasing. Total hysterectomy with bilateral salpingo-oophorectomy remains the standard therapy for early endometrial cancer [1]. However, doctor and patient attitudes towards radical cancer treatment methods, especially in young women of reproductive age, have been noticeably changing [1–4]. Women expect doctors to apply fertility-sparing therapy, if possible. Early endometrial cancer cases treated with preservation of reproductive function methods have been reported [5]. We present a case of a patient who conceived spontaneously and delivered a healthy newborn after hormonal treatment of early endometrial cancer. A 29-year-old female patient, nullipara, obese (body mass index (BMI) 32.1 kg/m2), presented to her gynecologist with a complaint of irregular, heavy bleeding. For the last year the menstrual pattern was irregular, every 30–60 days, hypermenorrhea lasting up to 14 days. An ultrasound examination revealed endometrial hypertrophy and polyp suspicion. The patient underwent diagnostic dilation and curettage. Histopathology revealed endometrial hyperplasia with atypia with adenocarcinoma foci (Figure 1). Magnetic resonance imaging and chest X-ray excluded more advanced cancer. Treatment options and the risk of cancer progression in case of saving childbearing potential were discussed with the patient, who eventually chose fertility-sparing therapy. She was strongly advised to lose weight with the help of a professional dietician. The patient was treated with high-dose oral progesterone, megestrol acetate 160 mg/day for 6 months after inserting the levonorgestrel intrauterine system (LNG-IUD). Endometrial curettage was performed after removing the levonorgestrel intrauterine system after 6 months. The histopathological examination revealed endometrium with decidual transformation. Mostly the endometrial glands were inactive. Single glands showed signs of hyperplasia without direct atypia. The assessment of atypia was difficult because of the gestagen influence (Figure 2). By that time she had reduced her weight by 30 kg (BMI 22 kg/m2). Then she was given estrogen-progesterone therapy to determine whether the pathological changes of the endometrium depended on the hormonal cycle. Although giving estrogen after a partial response does not seem to be the correct mode of treatment, we applied this treatment on purpose after the suggestion of the histopathologist. After half a year with the LNG system the endometrium showed a few residual foci of hyperplasia along with marked decidual transformation (Figure 2). We wanted to see if these changes would remain during the normal cycle or be shed during menstruation. Because the patient had an irregular menstruation pattern we gave her estradiol (day 5–25 of cycle) and norethisterone 5 mg (day 15–25 of cycle) for three months as part of the diagnostics. Repeat curettage after this treatment showed similar histopathological status and the residual foci did not progress to adenocarcinoma. Figure 1 Pre-therapy. Endometrial glands with neoplastic transformation (H + E, 100×) Figure 2 Post-therapy with high-dose systemic progesterone and local LNG-IUD for 6 months. Stroma with decidual transformation (drug-induced). Hyperplasia within the glandular tubes and on the endometrium surface – foci of residual hyperplasia (H + E, ... The patient was advised to conceive without delay. She was administered dydrogesterone 10 mg/day from day 14 until 28 of each cycle. Spontaneous pregnancy was obtained after 6 months and the patient delivered vaginally a full-term healthy female child. The placenta was not examined histopathologically as the patient delivered in another hospital. After the puerperium the levonorgestrel-releasing intrauterine device was inserted again. The patient is under careful surveillance for possible recurrence of disease. A review of the literature shows that hormonal treatment in grade 1 FIGO I adenocarcinoma without myometrial invasion is safe and can be discussed with patients willing to spare their fertility. Proper selection for fertility-preserving therapy requires diagnostic accuracy. Fertility-sparing therapy can be recommended to patients with early-stage, well-differentiated endometrial carcinoma (FIGO stage IA, Grade 1), presenting no ovarian tumors or metastases, no suspected lymph nodes, and no contraindications for endocrine therapy. Aggressive tumors such as papillary serous, clear cell adenocarcinoma, adenosquamous carcinoma and carcinosarcomas are contraindications for conservative management, and patients with these tumor types should be discouraged from attempting conservative treatment with hormones [6]. The current FIGO classification (2009) for endometrial cancer divides stage I into IA and IB, depending on the depth of myometrial invasion (MI). It is not always possible to evaluate it in the material from dilation and curettage (D&C). The best method of assessing the myometrial invasion and extrauterine spread before surgery is contrast-enhanced magnetic resonance imaging (MRI) [7]. The D&C is preferred to endometrial biopsy and seems to comply with the need for thorough evaluation of grade and occult malignancy [6]. Evaluation of the endometrial tissue should determine the lymphovascular space invasion (LVSI), which is considered a risk factor for lymph node metastasis. A literature search revealed that in case of LVSI the incidence of pelvic lymph node involvement grows from 7% to 27% and the 5-year survival rate decreases from 86% to only 61% of patients [8]. The first-line hormonal treatment for early endometrial cancer is medroxyprogesterone acetate (MPA) (dosage 200–800 mg/day) or megestrol acetate (MA) (10–400 mg/day), which inhibit the estrogen receptor and endometrial cell mitosis, promote apoptosis and induce secretory endometrium [9]. Mostly, 6 months of continuous therapy is enough to obtain remission, although there are cases with a 9-month hormonal treatment [10]. Our patient also did not respond completely after 6 months, despite the fact that she received combined therapy: megestrol acetate and the LNG-IUD. We obtained the resolution of adenocarcinoma foci, but the residual foci of atypical hyperplasia were still present. Although it seemed risky, with patient consent and wish and after thorough information, the chosen strategy was to conceive as soon as possible. Only one similar situation has been published. There is a report from a prospective study in which women were encouraged to conceive before the complete response to hormonal treatment. Remission was obtained by means of a low-dose cyclic natural progestin therapy (200 mg/day from day 14–25). The response rate was 57% and 43% of women conceived, of which 8 were in persistent disease or partial response. Another 3 complete responses were obtained after the delivery [11]. In conclusion, the case illustrates the favorable outcome of pregnancy after high-dose systemic and local progesterone therapy in early stage focal adenomatous endometrial carcinoma with atypical hyperplasia. Six months of continuous therapy and 6 months of cyclical progesterone therapy may achieve a good endometrial response for resolution of focal endometrial carcinoma, and this may favor implantation after the risk factors such as obesity have been controlled.

We present a rare case of 23-year-old patient with metastatic choriocarcinoma that presented life threatening abdominal bleeding from liver metastases shortly after initiation of treatment with chemotherapy and was treated by emergency embolization of the hepatic vessels. Although the bleeding was controlled, the patient succumbed to the disease on the 15th day after admission. Conclusions: Incontrollable hemorrhagic complications are the most common cause of death in choriocarcinoma metastatic patients. Angioembolization is an effective way of ceasing the bleeding and a potentially life saving measure.

Introduction Malignant tumours are rarely diagnosed during pregnancy, and their prevalence range from 2.4% to5.7%. Ovarian cancer is ranked fifth of all types of cancer and second of all genital cancers diagnosed during pregnancy. In most cases, the course of this disease is symptomless, and usually initial diagnose is made during routine ultrasound examinations. Management of ovarian cancer during pregnancy is a great challenge due to the fact that no clear standards of treatment have been developed so far. The objective of this work This work presents three clinical cases of patients suffered from ovarian cancer diagnosed during pregnancy. , a review of the literature, and the possible therapeutic options. Results Three different clinical scenarios in patients with ovarian cancer diagnosed during pregnancy has been presented. In addition we reviewed current diagnostic and therapeutic algorithms in patients with ovarian cancer and co-existing pregnancy was made. Conclusions Approximately 5% of diagnosed ovarian tumours are malignant. There are no treatment standards in the case of ovarian cancer during pregnancy. Both surgical treatment and the subsequent chemotherapy in the 2nd trimester of pregnancy appear to be safe for the mother and the child. However, the potential risks and benefits associated with the treatment have to be thoroughly analysed on a case-by-case basis, to establish diagnostic and treatment algorithms optimal for every patient.

The HPV-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) has been shown to induce a robust immune response in women aged 15–55 years (103514/NCT00196937). This follow-up study is the first report of persistence of immune response and safety profile through 48 months after vaccination in women aged 15–55 years. In this open-label, age-stratified Phase III study in Germany and Poland (105882/NCT00196937), healthy women aged 15–55 years received 3 doses of HPV-16/18 AS04-adjuvanted vaccine at 0, 1 and 6 months. Anti-HPV-16/18 seropositivity rates and geometric mean antibody titers (GMTs) were assessed by enzyme-linked immunosorbent assay (ELISA) in women aged 15–25 (n = 168), 26–45 (n = 186) and 46–55 years (n = 177) from the time of first vaccination through 48 months. At Month 48, all subjects were seropositive for anti-HPV-16 antibodies and 99.4% were seropositive for anti-HPV-18. Antibody kinetics were as previously reported, with peak response at Month 7 followed by a gradual decline tending towards a plateau in all age groups. Anti-HPV-16/18 GMTs were sustained at Month 48 in all age groups, including women aged 46–55 years in whom GMTs were respectively 11-fold and 5-fold higher than natural infection levels. The vaccine exhibited a clinically acceptable safety profile in all age groups. In summary, the HPV-16/18 AS04-adjuvanted vaccine induces high and sustained immune responses in women aged 15–55 years, with antibody levels remaining several-fold higher than natural infection levels for at least 4 years after the first vaccine dose.

Estrogen as a potential factor of ovarian carcinogenesis, acts via two nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), but the cellular signal pathways involved are not completely clear so far. In this study we have described the expression of ERα, detected by immunocytochemistry in 11 ovarian carcinoma cell lines and by immunohistochemistry in 43 Federation Internationale des Gyneacologistes et Obstetristes stage III ovarian carcinoma specimens prepared before and after treatment with cisplatin-based schemes. For cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma, analysis of cisplatin sensitivity in 11 ovarian carcinoma cell line was also performed. The strong nuclear ERα expression was only shown in the single A2780P cell line. Expression of ERα in tissue specimens did not reveal any correlations between histopathological parameters (histologic type and grading). We demonstrated a significant association with ERα expression in specimens from primary laparotomies (PL) and cause–specific survival. In the cases terminated by death of the patient, overall immunoreactivity score of ERα expression at PL was significantly lower than in surviving patients. In addition, Kaplan-Meier analysis revealed significantly shorter overall survival time and progression-free time in cases with lower immunoreactivity score of ERα expression at PL. Our findings support the hypothesis that aberrant hormone activity, by way of altered receptor expression, might be an important factor in the malignant transformation of ovarian cancer.

Objective To assign cutoff values for human chorionic gonadotropin (β-hCG) in pretreatment and after one methotrexate (MTX) cycle and determine its correspondence to the number of MTX cycles in successfully treated ectopic pregnancy. Design Retrospective study. Setting Polish university hospital. Patient(s) 68 women with ectopic pregnancies who qualified for medical treatment. Intervention(s) A single-dose of MTX (50 mg/m 2 ) repeated every 7 days, plus laparoscopy in cases of tubal rupture or increased (≥50% over 1 week) β-hCG concentration. Main Outcome Measure(s) Resolution of serum β-hCG without the necessity of laparoscopy. Result(s) Success rate was 78% (53 of 64 women). The medians of pretreatment β-hCG levels in the groups treated successfully and unsuccessfully (943 vs. 3085 mIU/mL) and after the first dose of MTX (564 vs. 4049 mIU/mL) were statistically significantly different. The decrease in β-hCG level after one MTX dose differed statistically significantly only in successfully treated women. The receiver operating characteristic (ROC) curve cutoff value in the success group indicated an initial β-hCG level of 1790 and 1218 mIU/mL after one MTX cycle. The median of β-hCG titer was not statistically different in patients requiring one or more treatment cycles. Conclusion(s) When the β-hCG level is >1790 mIU/mL, the MTX treatment of ectopic pregnancy is at risk of failure. However, the initial β-hCG titer is not a predictor of the number of MTX cycles that can guarantee a successful outcome.

After the discovery of the role human papilloma virus (HPV) plays in the development of cervical cancer we are witnesses to a change in the conception and interpretation of cervical cancer prevention processes. Primary prevention gained a new tool in the form of HPV vaccines. Secondary prevention, i.e. detection of cervical intraepithelial neoplasia (GIN), acquired a new diagnostic method--the HPV test. Studies were initiated in order to determine the usefulness of HPV tests in cervical cancer prevention and screening. They revealed that the DNA HPV test used in screening has higher sensitivity in CIN detection than PAP smear and that HPV-negative patients are better and longer protected against developing cervical cancer in comparison to women with normal PAP smear results. HPV tests also possess a predictive value, which detects women more susceptible to developing cervical cancer in the future. PAP smear does not have a predictive value. Instead, it only detects a presence or an absence of neoplasia at that particular time. These results clearly indicate that the era of classic PAP smear is indeed coming to an end, replaced by a new primary CIN screening tool--HPV test. The entire cervical cancer screening system must therefore be redefined and reorganized.

Resistance to cis- or carboplatin represents the principal cause of therapeutic failures in ovarian carcinoma. The phenomenon of resistance to platinum-based drugs is partly related to expression of metallothionein (MT) and of glutathione S-transferase pi (GST-pi), but opinion on the subject is discordant. Documentation of a negative predictive effect of MT and GST-pi expression for the therapy employing platinum-based drugs would permit to select resistant cases in which other therapeutic approaches could be employed. The present study aimed at examining the relation between intensities of MT and GST-pi expressions in ovarian carcinomas and dynamics of the clinical course in the neoplastic disease in a group of cisplatin-treated patients. The analyses were performed on samples of ovarian carcinoma originating from 43 first-look laparotomies (FLLs) and, in 30 cases, from second-look laparotomies (SLL) from the same patients. Immunohistochemical reactions were performed on paraffin sections of studied tumors, using monoclonal antibodies to MT and GST-pi. The calculations showed that in cases with augmented expression of MT, mortality was higher. On the other hand, augmented expression of GST-pi predisposed to more frequent relapses, deaths and progression of the tumor. Kaplan-Meier analysis showed that a significantly shorter survival time was linked to cases of higher expression of MT at FLL and of higher expression of GST-pi at FLL, whereas a shorter progression-free time was manifested by cases with higher expression of GST-pi at FLL. The performed investigations indicate that augmented expressions of MT at FLL and GST-pi at FLL in ovarian cancer represent an unfavourable predictive factor in cisplatin-treated patients.

Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogenesis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53-TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53-WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53.

Objective: Numerous studies suggest that cyclooxygenase-2 (COX-2) is overexpressed in cancer. Our objective was to investigate the relationship between COX-2 expression in ovarian carcinoma and clinicopathological factors. An emphasis was put on the association with the new pattern of tumorigenesis that divides tumors into type I – less aggressive, and type II – more aggressive one. The prognostic significance of COX-2 expression was evaluated. Methods: Ovarian cancer tissues were obtained from 65 patients in FIGO III stage (23 with type I and 42 with type II ovarian cancer). COX-2 expression was evaluated by immunohistochemistry. The statistical analysis was performed in order to assess the connection between COX-2 expression and characteristic factors of ovarian cancer patients as well as the new division for type I and type II ovarian cancer. Results: COX-2 expression was detected in 91% of tissue samples. It was markedly elevated in well differentiated tumors (p=0.0041). The platinum - resistant tumors had significantly higher expression of COX-2 (p=0.0337). There was no difference between COX-2 expression in type I and type II ovarian cancer (p=0.6720). The COX-2 staining was not associated to age, CA125 level, the presence of ascites or any special histological type. An increased expression of COX-2 was an unfavorable prognostic factor for overall survival (p=0.0369) and progression-free survival (p=0.0218). Multivariate analysis confirmed that COX-2 overexpression is an independent unfavorable prognostic factor of shorter progression-free survival (p=0.048). Conclusions: COX-2 expression is an unfavorable prognostic factor for progression-free survival and overall survival in ovarian cancer. There is no relationship between COX-2 expression in ovarian cancer tissue and the examined model of ovarian cancer pathogenesis.

Background: In patients with Ovarian Cancer (OvCa) exosomes released by tumor cells are present in the plasma and could be involved in tumor progression. This study examines the association between the exosome presence/protein content in plasma of OvCa patients and disease outcome, response to standard therapy and/or tumorresistance to therapies in patients studied at diagnosis and also serially during and after therapy. Design and methods: Exosomes were purified from OvCa patients’ plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC) using ultracentrifugation. Exosomes were visualized by scanning electron microscopy. Their protein content was measured. The presence of MAGE 3/6 and TGF-β1 in exosomes was evaluated in Western blots. Results: The OvCa patients’ plasma contained higher levels of exosomal proteins (p

Degradation of the extracellular matrix and basement membrane is a critical step in tumor progression. Matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP 2) act in a coordinated manner to form an integrated system involved in ovarian cancer (OC) progression. In this study, the authors describe the expression of TIMP-2 detected by immunohistochemistry in 6 OC cell lines and in 43 malignant epithelial ovarian tumors (in tumor and stromal compartments) in sections originating from primary laparotomies. No significant correlations between overall and progression-free survival and TIMP-2 expression in tumor compartment were observed. The analysis demonstrated a significant association between enhanced stromal expression of TIMP-2 and better clinical response to cisplatin- and paclitaxel-based chemotherapy. Increased expression of TIMP-2 in the stromal compartment and simultaneous overexpression in both stromal and tumor compartments strongly correlated with increased survival. No significant correlations were found in vitro between resistance to cisplatin, paclitaxel, or topotecan and the expression of TIMP-2 in the OC cell lines, suggesting stromal influences on tumor chemoresistance in the physiological environment. This study supports the concept of TIMP-2 expression in the stromal compartment of OC as a promising marker of prognosis and response to cisplatin- and paclitaxel-based chemotherapy in OC patients.

The optoelectronic method is one of the most promising concepts of biophysical program of the diagnostics of CIN and cervical cancer. Objectives of the work are evaluation of sensitivity and specificity of the optoelectronic method in the detection of CIN and cervical cancer. The paper shows correlation between the pNOR number and sensitivity/specificity of the optoelectronic method. The study included 293 patients with abnormal cervical cytology result and the following examinations: examination with the use of the optoelectronic method — Truscreen, colposcopic examination, and histopathologic biopsy.Specificity of the optoelectronic method for LGSIL was estimated at 65.70%, for HGSIL and squamous cell carcinoma of cervix amounted to 90.38%. Specificity of the optoelectronic method used to confirm lack of cervical pathology was estimated at 78.89%.The field under the ROC curve for the optoelectronic method was estimated at 0.88 (95% CI, 0.84–0.92) which shows high diagnostic value of the test in the detection of HGSIL and squamous cell carcinoma.The optoelectronic method is characterised by high usefulness in the detection of CIN, present in the squamous epithelium and squamous cell carcinoma of cervix.

This pooled analysis of data from four Phase III clinical trials was undertaken to assess the correlation between levels of anti-human papillomavirus (HPV)-16/18 antibodies in serum and cervicovaginal secretions (CVS) in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Serum and CVS samples were collected from a subset of women aged 10-65 years (N=350) at pre-specified time-points from 7 to 36 months post-vaccination. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay. Pearson correlation coefficients between serum and CVS antibody levels, standardized for total immunoglobulin G, were calculated at each time-point in women with detectable antibodies in both serum and CVS. All subjects had seroconverted at Month 7 and remained seropositive through Month 36 for both antigens. Geometric mean titers of anti-HPV-16/18 antibodies in serum were substantially higher at all time-points than those in a control group of women who had cleared a natural HPV infection in another trial. In women with detectable antibodies in both serum and CVS, good correlation was seen between HPV-16/18 antibody levels at all time-points (Pearson correlation coefficient: 0.84-0.92 for HPV-16 and 0.90-0.91 for HPV-18). The strong correlation between levels of HPV-16/18 antibodies in serum and CVS up to 36 months post-vaccination in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine supports transudation of serum antibodies as the mechanism by which antibodies are introduced into CVS. These CVS antibodies may play a role in the protective efficacy of this vaccine.

The immunogenicity and safety of an HPV-16/18 AS04-adjuvanted vaccine were assessed in women aged 26–55 years and compared with women aged 15–25 years in a Phase III, non-randomised, open-label, age-stratified study. Overall the vaccine was well tolerated and 100% seropositivity was achieved 1 month after the third dose in all age groups. There was a high correlation between HPV-16 and HPV-18 antibody levels (IgG) in cervicovaginal secretions and sera, regardless of age. The HPV-16/18 AS04-adjuvanted vaccine induces a robust and persistent immune response in women >26 years of age and generates antibodies that transudate through the cervix epithelium.

Purpose: Cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma. ABCC2 is commonly localized in apical cell membranes and could confer cisplatin resistance. Here, we show that ABCC2 can be localized in the cytoplasmic membrane as well as in the nuclear membrane of various human tissues including ovarian carcinoma cells. Experimental Design: For the subcellular detection of ABCC2, immunohistochemistry was done using 41 Federation Internationale des Gynaecologistes et Obstetristes stage III ovarian carcinoma specimens prepared before treatment with cisplatin-based schemes and 35 specimens from the same group after chemotherapy. Furthermore, 11 ovarian carcinoma cell lines as well as tissue microarrays consisting of various human tissues were analyzed. Results: Nuclear membranous localization of ABCC2 was associated with response to first-line chemotherapy at primary (P = 0.0013) and secondary surgery (P = 0.0060). Cases with relapse showed higher nuclear membrane expression at primary (P = 0.0003) and secondary surgery (P = 0.0024). Kaplan-Meier analyses showed that weak nuclear membrane ABCC2 expression before treatment was associated with significantly longer overall (P = 0.04) and progression-free survival (P = 0.001); following chemotherapy, it correlated with significantly longer progression-free survival (P = 0.038). Tissue microarrays confirmed nuclear membranous localization of ABCC2, in particular, in poorly differentiated cells. In ovarian carcinoma cells, it correlated with resistance against cisplatin, whereas localization in the cytoplasmic membrane did not. Conclusions: ABCC2 confers resistance to cisplatin of ovarian carcinoma in cell culture systems and in clinics when expressed in the nuclear membrane. Thus, ABCC2 localization can predict platinum therapy outcome. Furthermore, expression of ABCC2 in nuclear membranes in human tissues is specific for poorly differentiated cells including stem cells.

Elevated metallothionein (MT) expression in ovarian cancers treated with cisplatin-based schemes represents an unfavorable prognostic index. MT expression is significantly higher in tumor samples obtained after chemotherapy. The present study aimed at examining MT expression in ovarian carcinoma cells sensitive (A2780) or resistant (A2780RCIS) against platinum drug treatment as well as examining effects of exposure to cisplatin on MT expression. Subcellular expression of MT was evaluated also in samples originating from 73 ovarian tumors. Cisplatin-resistant A2780RCIS cells were exposed to increasing cisplatin concentrations, and the subcellular expression of MT was determined by immunocytochemistry. The studies demonstrated that cisplatin-resistant A2780RCIS cells exposed to cisplatin typically manifested a nuclear MT expression. The study demonstrated also that exposure to cisplatin was paralleled by growing MT expression in cell nuclei. The nuclear expression of MT was also found to be specific for ovarian cancers of poor clinical outcome. No relationship could be demonstrated between cytoplasmic expression of MT and clinical variables. Nuclear MT expression is induced by cisplatin and seems to protect DNA in the cells from toxic effects of the drug.

An obstacle in chemotherapy of ovarian cancer is the development of drug resistance. Taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) was found to be overexpressed in a paclitaxel-resistant ovarian carcinoma cell line. However, clinical impact of TRAG-3 in ovarian carcinoma has not been demonstrated previously. For demonstration of potential clinical impact of TRAG-3, immunohistochemistry was applied to determine TRAG-3 protein expression in specimens obtained from ovarian carcinoma patients (n=37) who received a paclitaxel-based chemotherapy at two different time points, initial laparotomy before chemotherapy, and secondary cytoreduction after chemotherapy. The TRAG-3-specific immunohistochemical staining was correlated with clinical outcome. In ovarian carcinoma specimens obtained at the initial laparotomy, an advantage in overall (P < 0.001) and progression-free (P = 0.003) survival for patients with weak TRAG-3 expression could be demonstrated. Tumor specimens excised at secondary cytoreduction procedure were not predictive for clinical outcome. In summary, TRAG-3 was found to be a prognostic factor for the prediction of clinical outcome after the application of paclitaxel-based chemotherapy.

High cytoplasmic expression of maspin was described in ovarian cancers of shorter survival rates. Until now, no relationship has been described between expression of maspin and sensitivity to cisplatin in ovarian cancers. This study aimed at examining the relationship between expression of maspin, detected by immunohistochemistry and clinical response to cisplatin in ovarian cancer cases as well as the in vitro sensitivity to cisplatin of 11 ovarian cancer cell lines. The analyzes were performed on 73 samples of ovarian cancer and on A2780P, A2780RCIS, CAOV-3, EFO 21, EFO 27, ES-2, Mdah 2774, OAW 42, OVCAR-3, PA-1, and SKOV-3 ovarian cancer cells. Cytoplasmic maspin expression in studied cells significantly correlated with cisplatin sensitivity. A significantly shorter overall survival and progression-free survival was associated with lower cytoplasmic maspin expression at first-look laparotomies and nuclear maspin expression and secondary cytoreductions. Higher nuclear maspin at first-look laparotomies expression was specific for cases of complete response. In the study, the elevated expression of maspin was shown to be typical for cisplatin-sensitive ovarian cancers.

Background: Ectonucleotidases CD39/CD73 have been reported to play an important role in functional supression of various immune cells via adenosine that is generated locally in the tumor microenvironment. In patients with ovarian cancer (OvCa) exosomes released by tumor cells (TEX) are abundant in body fluids, including the plasma or ascites and may be involved in tumor progression. Based on the observations suggesting that TEX carry proteins that are expressed on tumor cells from which TEX originate, we hypothesized that CD39+ and CD73+ TEX could deliver these enzymes to distant immune cells. Adenosine produced fom ATP in the presence of TEX could suppress functions of these cells or elevate suppressor activity of regulatory T cells (Treg) , The aim of the study was to: (1) investigate the expression and clinical significance of CD39, CD73, adenosine deaminase (ADA) and CD26 in OvCa tissues and in TEX isolated from OvCa body fluids; (2) determine whether OvCa TEX metabolize exogeneous ATP to adenosine. (3) characterize the molecular profile of TEX; and (4) test whether OvCa TEX can suppress activities of NK cells and up-regulate suppressive activity of Treg. Methods: The expression of CD39, CD73, ADA and CD26 in OvCa tissues was determined by immunohistochemistry (IHC). The relationship between expression of these enzymes and clinicopathological characteristics was analyzed. TEX were isolated from supernatant of two OvCa cell lines (A2780, SKOV-3) and from the patients' plasma by exclusion chromatpgraphy followed by ultracentrifugation, as previously described.. Western blots were used for molecular characterization of TEX. NK cells and Treg were separated from the PMBC of normal donors and co-cultured with TEX. The phenotype of NK cells and Treg was evaluated by flow cytometry. ATP hydrolysis was measured using a luciferase detection assay. Results: By IHC in tissue sections, 70% of tumor cells were CD39+, 77% were CD73+ and 100% were CD26+ADA+.Expression levels of the ectonucleotidases varied from strong to moderate, and patients with a more advanced disease stage had tumors showing strongest CD73 expression (p Conclusion: Similar to OvCa tumor cells in tissue exosomes isolated from the plasma of OvCa patients were found to carry enzymatically-active ectonucleotidases and to produce extracellular adenosine. These exosomes were capable of down-regulating NK cell functions and up-regulating Treg activity in vitro. The same TEX-mesiated mechanisms could contribute to tumor-induced immune suppression characteristic of OvCa and resulting in tumor immune escape and OvCa progression. Note: This abstract was not presented at the conference. Citation Format: Marta E. Szajnik-Szczepanski, Magdalena Derbis, Michal Lach, Paulina Patalas, Marcin Michalak, Hanna Drzewiecka, Marta Glura, Ewa Nowak-Markwitz, Marek Spaczynski, Theresa L. Whiteside. The adenosine pathway in ovarian carcinoma: Tumor cells and tumor-derived exosomes express CD39 and CD73 ectonucleotidases, produce adenosine and mediate immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A79.

Introduction Paraneoplastic neurological syndromes (PNS) are neurologic deficits triggered by an underlying remote tumor. PNS can antedate clinical manifestation of ovarian malignancy and enable its diagnosis at an early stage. Interestingly, neoplasms associated with PNS are less advanced and metastasize less commonly than those without PNS. This suggests that PNS may be associated with a naturally occurring antitumor response. Methods We review the literature on the diagnosis, pathogenesis and management of PNS associated with ovarian tumors: paraneoplastic cerebellar degeneration (PCD) and anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. An approach to the diagnostic workup of underlying tumors is discussed. Results PCD can precede the manifestation of ovarian carcinoma. Anti-NMDAR encephalitis in young women appears often as a result of ovarian teratoma. Since ovarian tumors and nervous tissue share common antigens (e.g., cdr2, NMDAR), autoimmune etiology is a probable mechanism of these neurologic disorders. The concept of cross-presentation, however, seems insufficient to explain entirely the emergence of PNS. Early resection of ovarian tumors is a significant part of PNS management and improves the outcome. Conclusions The diagnosis of PNS potentially associated with ovarian tumor indicates a need for a thorough diagnostic procedure in search of the neoplasm. In some patients, explorative laparoscopy/laparotomy can be considered.

A major obstacle in treatment of ovarian cancer is intrinsic or acquired drug resistance causing failure of chemotherapy followed by a poor clinical outcome. Drug resistance of ovarian carcinoma can be caused by dysregulation of cellular factors involved in regulation of apoptosis and DNA repair pathways. In this study, 73 ovarian carcinoma specimens obtained before and after chemotherapy were analysed by immunohistochemistry for expression of seven proteins playing an important role in regulation of DNA mismatch repair and apoptosis. The prognostic significance of these proteins in the meaning of overall and progression-free survival was evaluated in univariate and multivariate analysis. Bcl-x L , hMSH2, caspase-3, p21 and p53 displayed prognostic importance in univariate analysis. Furthermore, it was demonstrated that caspase-3 and p21 were also independent prognostic markers for both, overall and progression-free survival. In conclusion, these data indicate that analysis of proteins involved in DNA mismatch repair and apoptosis can be useful for prediction of clinical outcome in ovarian carcinoma patients.