Persistence of immune responses to the HPV-16/18 AS04-adjuvanted vaccine in women aged 15-55 years and first-time modelling of antibody responses in mature women: results from an open-label 6-year follow-up study.

OBJECTIVE: Evaluation of the long-term HPV-16/18 AS04-adjuvanted vaccine immunogenicity persistence in women. DESIGN: Multicentre, open-label, long-term follow-up (NCT00947115) of a primary phase-III study (NCT00196937). SETTING: Six centres in Germany and Poland. POPULATION: 488 healthy women (aged 15-55 years, age-stratified into groups: 15-25, 26-45, and 46-55 years) who received three vaccine doses in the primary study. METHODS: Immune responses were evaluated in serum and cervicovaginal secretion (CVS) samples 6 years after dose 1. Anti-HPV-16/18 geometric mean titres (GMTs) were measured by enzyme-linked immunosorbent assay (ELISA), and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) were recorded. MAIN OUTCOME MEASURES: Anti-HPV-16/18 seropositivity rates and GMTs 6 years after dose 1. RESULTS: At 6 years after dose 1, all women were seropositive for anti-HPV-16 and ≥97% were seropositive for anti-HPV-18 antibodies. GMTs ranged from 277.7 to 1344.6 EU/ml, and from 97.6 to 438.2 EU/ml, for anti-HPV-16 and anti-HPV-18, respectively. In all age groups, GMTs were higher (anti-HPV-16, 9.3-45.1-fold; anti-HPV-18, 4.3-19.4-fold) than levels associated with natural infection (29.8 EU/ml). A strong correlation between serum and CVS anti-HPV-16/18 levels was observed, with correlation coefficients of 0.81-0.96 (anti-HPV-16) and 0.69-0.84 (anti-HPV-18). Exploratory modelling based on the 6-year data predicted vaccine-induced anti-HPV-16/18 levels above natural infection levels for at least 20 years, except for anti-HPV-18 in the older age group (piecewise model). One vaccine-related and two fatal SAEs were reported. CONCLUSIONS: At 6 years after vaccination, immune responses induced by the HPV-16/18 AS04-adjuvanted vaccine were sustained in all age groups.

Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study.

BACKGROUND: Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. PATIENTS AND METHODS: A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. RESULTS: The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. CONCLUSIONS: Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer.

Toll-like receptors (TLRs) expressed on immune cells trigger inflammatory responses. TLRs are also expressed on ovarian cancer (OvCa) cells, but the consequences of signaling by the TLR4/MyD88 pathway in these cells are unclear. Here, TLR4 and MyD88 expression in OvCa tissues (n=20) and cell lines (OVCAR3, SKOV3, AD10, A2780 and CP70) was evaluated by reverse transcriptase-PCR, western blots and immunohistochemistry. Cell growth, apoptosis, nuclear factor-kappaB (NF-kappaB) translocation, IRAK4 and TRIF expression and cJun phosphorylation were measured following tumor cell exposure to the TLR4 ligands, lipopolysaccharide (LPS) or paclitaxel (PTX). Culture supernatants were tested for cytokine levels. TLR4 was expressed in all tumors, tumor cell lines and normal epithelium. MyD88 was detectable in tumor tissues and in 3/5 OvCa lines but not in normal cells. In MyD88(+) SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-kappaB pathway and promoted interleukin (IL)-8, IL-6, vascular endothelial growth factor and monocyte chemotactic protein-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with small interference RNA resulted in phosphorylated-cJun (p-cJun) downregulation and a loss of PTX resistance. In PTX-sensitive, MyD88(neg) A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect. Thus, TLR4/MyD88 signaling supports OvCa progression and chemoresistance, promoting immune escape.

Expression of aminopeptidase N/CD13 in human ovarian cancers.

Aminopeptidase N/CD13 (EC 3.4.11.2) is suggested to play a role in cancer cells invasion, and its activity can be inhibited using specific inhibitors. CD13 inhibitors evoke apoptosis of CD13-positive cancer cells. However, expression of CD13 has not been described in specimens obtained from ovarian carcinomas. Thus, in the present study, the expression of CD13 and its significance was examined in samples of ovarian cancers. The analyses were performed on sections originating from 73 tumor samples (43 from primary laparotomies [PL] and 30 from secondary cytoreductions [SCRs]). Immunohistochemical reactions were performed on paraffin sections of studied tumors, using monoclonal antibodies against CD13. The analysis demonstrated no relationships between the expression of CD13 on one hand and clinical variables and pathologic variables of the patients on the other hand. Expression of CD13 was demonstrated to be significantly more pronounced in samples obtained in PLs as compared to samples from SCRs (P < 0.001). Thus, the data indicate that a potential treatment of ovarian carcinoma with CD13 inhibitors should be performed before chemotherapy or in parallel to first-lapse chemotherapy.

Unfavorable prognostic value of CD24 expression in sections from primary and relapsed ovarian cancer tissue.

Expression of CD24 represents a poorly recognized, unfavorable prognostic factor. Expression of the protein is supposed to facilitate extravasation of tumor cells. Our study aimed at examination of prognostic significance of CD24 estimation in samples obtained from primary surgeries (PS) and secondary cytoreductions (SCR) (after chemotherapy) in ovarian cancer patients. The analyses were performed on sections originating from 73 tumor samples. Immunohistochemical reactions were performed on paraffin sections of studied tumors, using monoclonal antibodies against CD24. Kaplan-Meier's analysis showed that a significantly shorter overall survival time and progression-free time was demonstrated to characterize cases with cytoplasmic membranous expression of CD24 (CD24c-m) (P < 0.001). The calculations performed demonstrated also a significantly higher proportion of CD24c-m positive cases in sections from SCR as compared to that from PS (P= 0.04) and in cases of progressive disease as compared to complete response at PS and SCR (P= 0.002 and P= 0.05, respectively). Summing up, in this study, we have demonstrated a negative prognostic significance of a cytoplasmic membranous expression of CD24 in cases of ovarian cancer.

Topoisomerase 1A, HER/2neu and Ki67 expression in paired primary and relapse ovarian cancer tissue samples.

In the present study we examined prognostic value of immunohistochemical estimation of topoisomerase 1A (TOP 1A) and HER-2/neu expression in ovarian cancers treated with platinum-based drugs but not with topotecan and the relation between expression of these proteins on the one hand and intensity of proliferation (Ki67) on the other. The analyses were performed on 73 samples of ovarian carcinoma originating from 43 first-look laparotomies (FLL) and, in 30 cases, from secondary cytoreductions (SCR)(after chemotherapy) from the same patients. In paraffin sections immunohistochemical reactions were performed using antibodies directed to HER-2/neu, TOP 1A and Ki67. Kaplan-Meier's analysis disclosed a shorter overall survival time in cases with augmented expression of TOP 1A at FLL and with higher expression of Ki67 at SCR. A shorter progression-free time was detected in cases with higher proportion of Ki67 positive cells at FLL. No relationship could be disclosed between HER-2/neu expression and the studied clinicopathological parameters. The studies confirmed high value of Ki67 estimation. The augmented expression of TOP 1A was demonstrated to represent an unfavourable prognostic factor. Thus, in cases with elevated expression of TOP 1A application of topotecan-based therapeutic schemes should be considered.

The level of antibody against E6 HPV 16 oncoprotein in blood sera of women with chronic HPV 16 infection and cervical cancer.

UNLABELLED: The aim of this study was to estimate of the role of chronic HPV 16 infection and the presence of anti E6 HPV 16 in the initiation of the cancerogenesis process of cervical cancer. MATERIAL AND METHODS: The study included two groups of patients. The first group comprised 323 women observed for three consecutive years (1998-2000), in whom the presence of HPV 16 viruses was estimated by PCR, and the level of anti E6 HPV 16 antibodies was estimated in the plasma with ELISA. A similar test was performed in a group of 46 patients with cervical intraepithelial neoplasia (CIN), 91 patients with invasive cervical cancer and 22 women after hysterectomy and RTG-therapy. RESULTS: In 32 patients, chronic HPV 16 infection showed a steady rise in the mean absorbance level of anti E6 HPV 16 antibodies from 0.04 in 1998 to 0.06 in 2000, while in HPV-negative women the mean absorbance value was 0.03-0.04. Mean absorbance value in patients with CIN III and invasive cancer rose with advancing stage of the cancer process and lowered after completion of oncological treatment. The values were 0.14, 0.33 and 0.13, respectively. CONCLUSION: The persistence of chronic HPV 16 infection and accompanying steady rise in absorbance index caused by an increase in the level of antiviral antibodies are a clear warning signal preceding in time the histological process of cancerogenesis.

An ultrasonographic morphological index for prediction of ovarian tumor malignancy.

PURPOSE OF INVESTIGATION: A newly created ultrasonographic scale called the Poznan index as well as scales already well known (introduced by Sassone, De Priest and Lerner) were compared in our group of patients. METHOD: A morphological index was based on seven sonographic ovarian tumor features. Examinations on 686 patients were evaluated. Comparison of prognostic values of the Poznan index with other applied morphological indices in our group of patients was based on the area under receiver operating characteristic (ROC) curves. RESULTS: The cut-off level of the new index is 8 points. The new morphological index has a specificity of 77.0%, and negative and positive predictive values of 90.7% and 69.1%, respectively. It has a sensitivity of 86.7% and accuracy of 80.6%. The Poznan index proved its usefulness and superiority (AU ROC = 0.89). CONCLUSION: Using this morphological index it is possible to make a precise prognosis of ovarian tumor malignancy. It also makes it possible to make the right decision concerning the manner of surgical treatment.

[Gynecologic endoscopy in the greater region of Poland during 1988-1998]. / Endoskopia ginekologiczna w województwie wielkopolskim w latach 1988-1998.

The aim of the study was to analyze the state and development of the gynaecological endoscopy in the Wielkopolska region in years 1988-1998. The questionnaire included gynaecological and obstetrical departments of 31 hospitals: 1 academic center, 5 former regional hospitals and 25 small hospitals. At the end of 1998 35.5% of departments were equipped with laparoscopes and 9.7% with histeroscopes. There was an increase in the laparoscopic procedures from 151 to 832 estimated in these years, as well as from 181 to 314 hysteroscopies. The detailed analysis of procedures and dynamic of its increase according to the type of hospital is presented. The experience of the staff was also analyzed. We demonstrated the insufficient equipment in the region, in spite of the right tendencies in the spectrum of the endoscopic procedures and the experience of the physicians who perform laparoscopy and hysteroscopy.

[Ovarian cancer and endometriosis]. / Rak jajnika a endometrioza.

Endometriosis is a relatively common condition found in up to 29% of women undergoing laparotomies. The authors suggest that endometriosis could have undergone malignant change. They propose the criteria used to establish that a malignant tumor has develop in endometriosis: clear evidence of endometriosis should be found close to the tumor, the histopathological appearance should be such that origin of the tumor from endometriosis is plausible, no other primary site should be found. The authors consider that atypical endometriosis possesses a precancerous potential or is most frequently associated with endometrioid and clear cell carcinomas.

[Integrin alpha-6 in cervix neck squamous cell carcinoma HPV 16/18 positive and negative]. / Integryna alfa-6 w rakach plaskonablonkowych szyjki macicy HPV 16/18 pozytywnych i negatywnych.

In the present paper we study expression of alpha-6 integrin in normal paraepidermal epithelium, in CIN and in cervical invasive carcinoma HPV 16/18 positive and negative. The results suggest that alpha-6 integrin might be a marker for the evaluation of malignancy of squamous cell carcinoma. There is no correlation between the expression of alpha-6 integrin and the presence of HPV.

Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer.

PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

[Chorion carcinoma: failure of treatment]. / Rak kosmówki--niepowodzenie leczenia.

Between 1986-1998 in University Oncology Gynecology Department in Poznan, Poland were treated 23 women with choriocarcinoma. Despite of intensive chemotherapy 3 women were dead. In the report we present the history of this choriocarcinomas making effect to answer why our therapy was ineffective.

[Gestational trophoblastic disease: the epidemiological analysis of 342 cases]. / Rozrosty i nowotwory trofoblastu--analiza epidemiologiczna 342 chorych.

Between 1987-1996 dates were collected to assess frequency and risk factors for gestational trophoblastic disease in a case-control study of 342 women with trophoblastic tumors and 342 pregnant women admitted for deliveries or spontaneous abortion to University Hospitals in Poznan, Poland. Were analyzed the age of women obstetric history, place of live and repeat appearance of hydatidiform mole. The risk of trophoblastic disease increased with increase in maternal age and above third pregnancy. The risk independent of living in town or in the country. The second and more incident of hydatidiform mole was associated with greater risk of malignant sequele. The study of the pregnancy of gestational trophoblastic disease was led in Great Poland in the support on the date from all pathologic centres in this region and public demographic office. The frequently of hydatidiform mole was between 1987-1996 2.32 per 100,000 women, and 0.76 for 1000 live birth (1 HM for 1315 live birth). The frequently of choriocarcinoma was 0.08 per 100,000 women (and 0.38 per 10,000 live birth (1 CHA per 26,315 live birth).

Relationship between HPV infection of the cervix and blood serum levels of steroid hormones among pre- and postmenopausal women.

Human papillomaviruses (HPVs) are frequently present in anogenital lesions but little is known about their role in carcinogenesis. There are steroid hormone response elements in virus genomes that influence expression patterns of viral genes. Activity of the elements may contribute to development of neoplasia in case of hormone level anomalies. Our study was to determine whether the presence of HPV DNA in cervical smears correlates with abnormal levels, of steroid hormones in blood serum. One hundred women aged 40-62 participated in the tests and were divided into two groups: premenopausal and postmenopausal (45 and 55 individuals, respectively). Presence of HPV DNA in cervical smears was detected by PCR and Southern blot hybridisation. Progesterone and estradiol levels in blood serum were measured by radioimmunoassay. Our study showed a higher prevalence of HPV DNA in women with higher levels of progesterone in blood serum. A relationship between hormone level and HPV DNA prevalence should alert clinicians about using hormone contraceptives and hormone replacement therapy.

[Immunohistochemical examination oncogenic c-erb-b2, egf-r proteins and antioncogenic p53 protein in vulvar cancers HPV-16 positive and negative]. / Immunohistochemiczne oznaczanie aktywnosci proliferacyjnej oraz bialek onkogennych C-ERB-B2, EGF-R i bialka antyonkogennego p53 w rakach sromu i stanach przedrakowych sromu i pochwy HPV 16 pozytywnych i negatywnych.

In vulvar cancers HPV 16 positive, HPV 16 negative, and vulvar and vaginal precancerous status (VIN, VAIN) immunohistochemical technik onko- and antioncogenic proteins were evaluated. The contrary correlation between HPV 16 presence and overexpression p53 were detected. It suggest the heterogenic etiology of these cancers. There was payed attention to high activity of virus replication and intensive virion production in VAIN. Nontreated vaginal lesion may make difficult to obtain a positive cervical HPV infection treatment.

[Bone marrow involvement in ovarian cancer determined by immunohistochemical methods]. / Nachweis von Epithelzellen im Knochenmark von Patientinnen mit Ovarialkarzinomenunter Anwendung von immunhistochemischen Methoden.

Atypical epithelial cells in the bone marrow of patients with ovarian cancer were evaluated using immunohistochemical techniques. We investigated cytospin preparations of bone marrow taken from 9 women with benign ovarian tumors and 59 women with malignant ovarian tumors. Two monoclonal antibodies (NCL-C11 and NCL-CA 125) were used. With both antibodies we were able to detect keratin and CA 125 antigen expression in the bone marrow of 9 (18.4%) of the patients with ovarian cancer. With regard to the wide histological differentiation of ovarian carcinomas, the presence of atypical epithelial cells in the bone marrow was required as a prognostic factor for survival and relapses. This should be investigated in a larger study group.

[Bone marrow involvement in ovarian cancer by immunohistochemical assessment]. / Immunohistochemiczna analiza szpiku kostnego chorych z rakiem jajnika.

In the study below we introduced certain conclusions from bone marrow analysis in patient with ovarian cancer in the presence of epithelial cells. The study included cytological bone marrow slides taken from 31 patients. We analyzed the cellular antigen expression using immuno-histological chemistry technic with NCL-CA 125, NCL-EMA and NCL-C11 antibodies. In the material drived from 3 patients with advanced neoplastic changes, we detected the presence of cells that were stained positively. In order to define the actual frequency of cell presence with tested antigen expression in bone marrow as well as to signify the diagnostic and prognostic value of their detection requires a larger study group as well as using other examination technics such as PCR or transluscent photometry.

[Bowen's disease: one of the types of vulvar intraepithelial neoplasm (VIN) III (four case reports)]. / Choroba bowena--jedna z postaci VIN III (przedstawienie czterech sytuacji klinicznych).

Vulvar intraepithelial neoplasia has been considered a problem of postmenopausal years, but its frequency appears to be increasing among younger women. Bowen's disease is a form of VIN III carcinoma in situ, that may appear clinically as pigmented lesions. This pathology mostly concerns younger women, and is probably connected with human papilloma virus (HPV) infection. The incidence rate is very rare. During the last 15 years only four cases of Bowen's disease have been diagnosed and treated in Division of Gynecological Oncology in Poznan. In this paper we presented symptoms, diagnostic procedures, results of clinical and histopathologic evaluation as well as managements methods. Also the results of treatment and reports on follow-up visits have been discussed.