Human papillomavirus type distribution in cervical intraepithelial neoplasia grade 2/3 and cervical cancer in Portugal: a CLEOPATRE II Study.

OBJECTIVE: Cervical cancer is the third most frequent cancer in women, worldwide and etiologically associated with infection by human papillomavirus (HPV). Following the results of the first epidemiologic population-based CLEOPATRE study in Portugal, it was important to understand the HPV type-specific distribution in women with cervical intraepithelial neoplasia (CIN) grades 2 and 3 and invasive cervical cancer (ICC). METHODS: This was an observational, multicenter, cross-sectional study with retrospective data collection. Between January 2008 and May 2009, paraffin-embedded samples of histologically confirmed cases of CIN2, CIN3, and ICC were collected from the 5 regional health administrations in mainland Portugal. Eligible samples were sent to 2 central laboratories for histological reassessment and HPV genotyping. Prevalence estimates were calculated together with 95% confidence intervals. RESULTS: A total of 582 samples, 177 cases of CIN2, 341 of CIN3, and 64 of ICC, were included. The mean age of participants was 41.8 years (range, 20-88 years). The overall HPV prevalence was 97.9% with a higher prevalence of high-risk genotypes, particularly HPV 16. Multiple infections were observed in 11.2% of the cases. Human papillomavirus prevalence was 95.5% in CIN2, 99.4% in CIN3, and 96.9% in ICC. The 8 more frequent genotypes in order of decreasing frequency were HPV 16, 31, 58, 33, 51, 52, 18, and 35 in CIN2 and HPV 16, 31, 33, 58, 52, 35, 18, and 51 in CIN3. In ICC cases, the 12 detected HPV genotypes were HPV 16, 18, 31, 33, 45, 51, 52, 53, 56, 58, 59, and 73. However, HPV 53 and 73 were always associated to other high-risk genotypes. Human papillomavirus types 31, 51, 52, 56, and 59 were detected in 1 case each. CONCLUSIONS: Human papillomavirus prevalence and patterns of type-specific HPV positivity were comparable with other studies. Current HPV vaccines should protect against HPV genotypes responsible for 77.4% of ICC in Portugal.

Prevalence of human papillomavirus infection in women in Portugal: the CLEOPATRE Portugal study.

OBJECTIVE: Human papillomavirus (HPV) is responsible for a range of diseases, including cervical cancer. The primary objectives of the CLEOPATRE Portugal study were to estimate the overall and age-stratified prevalence of cervical HPV infection and to assess HPV prevalence and type-specific distribution by cytological results among women aged 18 to 64 years, who reside in mainland Portugal. MATERIALS AND METHODS: This cross-sectional population-based study recruited women aged 18 to 64 years, according to an age-stratified sampling strategy, who attended gynecology/obstetrics or sexually transmitted disease clinics across the 5 regional health administrations in mainland Portugal between 2008 and 2009. Liquid-based cytology samples were collected and analyzed centrally for HPV genotyping (clinical array HPV 2 assay) and cytology. Prevalence estimates were adjusted for age using 2007 Portuguese census data. RESULTS: A total of 2326 women were included in the study. The overall prevalence of HPV infection in the study was 19.4% (95% confidence interval, 17.8%-21.0%), with the highest prevalence in women aged 18 to 24 years. High-risk HPV types were detected in 76.5% of infections, of which 36.6% involved multiple types. The commonest high-risk type was HPV-16. At least 1 of the HPV types 6/11/16/18 was detected in 32.6% of infections. The HPV prevalence in normal cytology samples was 16.5%. There was a statistically significant association between high-risk infection and cytological abnormalities (P < 0.001). CONCLUSIONS: This is the first population-based study to quantify and describe cervical HPV infection in mainland Portugal. This study provides baseline data for future assessment of the impact of HPV vaccination programs.

Epoetin alfa improves anemia and anemia-related, patient-reported outcomes in patients with breast cancer receiving myelotoxic chemotherapy: results of a European, multicenter, randomized, controlled trial.

PURPOSE: To evaluate the effects of epoetin alfa on patient-reported outcomes (PROs) in patients with breast cancer receiving myelotoxic chemotherapy. MATERIALS AND METHODS: Women with hemoglobin concentrations ≤ 12.0 g/dl and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-3 were randomized 1:1 to receive epoetin alfa (10,000 IU 3 times weekly) or best standard care (BSC) during chemotherapy. The primary endpoint was the change from baseline in the total anemia subscale assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire after 12 weeks of treatment. The fatigue and nonfatigue subscales from the FACT-An, the Cancer Linear Analog Scale (CLAS), hemoglobin changes, ECOG PS score, tumor response, overall survival, and safety also were evaluated. RESULTS: Of 223 patients randomized, 216 constituted the modified intent-to-treat population. Percentage changes in the total anemia subscale of the FACT-An were significantly different between epoetin alfa treatment (14.2%) and BSC (-0.5%; p = .002), favoring epoetin alfa; so were changes in the FACT-An fatigue subscale (epoetin alfa, 17.5%; BSC, -0.9%; p = .003) and nonfatigue subscale (epoetin alfa, 8.8%; BSC, 0.2%; p = .008). Similar results were observed with the CLAS. Hemoglobin concentrations > 12 g/dl were more common with epoetin alfa (62.0%) than with BSC (27.6%). Tumor response, ECOG PS score, 12-month survival rate, and the incidence of serious treatment-emergent adverse events were similar between groups. CONCLUSION: Early intervention with epoetin alfa was well tolerated and improved anemia-related PROs in patients with breast cancer receiving myelotoxic chemotherapy.

Neoadjuvant chemotherapy in advanced vulvar cancer.

INTRODUCTION: Locally advanced tumors of the vulva represent approximately one third of all vulvar cancers. Therapeutic options include chemoradiation, radiotherapy, and neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: Analysis of 3 NACT schemes, bleomicine, paclitaxel, and 5-fluorouracil/cisplatin, used in patients with locally advanced vulvar tumors in a 12-year period. The following parameters were evaluated and compared between regimens: age, initial tumor size, inguinal involvement, histological type, toxicities, response to treatment, surgery performed after NACT, and overall survival. RESULTS: Of the 25 patients included, 10 underwent an NACT regimen with bleomicine (Group A); 5, with paclitaxel (Group B); and 10, with a combination of 5-fluorouracil/cisplatin (Group C). In Group A, there was a 60% response rate. Mortality was 70%, with an overall survival rate of 70%, 40%, and 30% at 12, 24, and 60 months, respectively. The mean (SD) survival was 46.7 (15.4) months. In Group B, the response rate was 40%, with an 80% mortality rate and a survival rate of 60% and 20% at 12 and 24 months, respectively. The mean (SD) survival was 17.0 (3.8) months. In Group C, 20% of the responses were observed and the mortality was 90%, with an overall survival rate of 10% at 12 and 24 months and a mean (SD) survival of 7.6 (2.0) months. CONCLUSION: The best response and overall survival rates were achieved in Group A with the NACT scheme of bleomicine.

Influence of normal mammary epithelium on breast cancer progression: the protective role of early pregnancy.

AIMS AND BACKGROUND: The microenvironment has a well recognized role in breast cancer progression. Despite different theories, the mechanism of early pregnancy protection in mammary carcinogenesis is unknown. Since pregnancy is responsible for mammary gland differentiation, we tested the hypothesis that differentiated mammary epithelial cells may inhibit breast cancer progression. In other words, the protective role of early pregnancy could be due to the inhibitory influences of the more differentiated mammary tissue. METHODS: In order to test our hypothesis, we used 30 female Balb/c nude mice and MCF-7 cells of breast adenocarcinoma. The female mice were divided into two test groups, group I (GI) and group II (GII), and a control group. In GII, the animals were submitted to epithelial removal in the left fourth inguinal mammary gland at 3 weeks of age. Both groups were given continuous hormonal treatment to simulate the pregnancy development of the mammary gland. Two million MCF-7 cells were then injected into the fourth inguinal mammary gland (GI) or in the respective cleared mammary fat pad (GII). Five weeks later the mice were sacrificed and their tumors removed. Tumor development rates and tumor volumes were determined and proliferation and apoptosis were evaluated by immunohistochemistry. RESULTS: Tumors of GII mice had a larger mean volume than those of GI mice (P = 0.001, Mann-Whitney U-test) and an apparent increase in proliferation, demonstrated by a higher staining intensity for proliferating cell nuclear antigen (PCNA). As tumors presented caspase 8 staining, there may be apoptotic activation involved in cell death, mainly through an extrinsic pathway. CONCLUSIONS: These results suggest that a differentiated intact mammary gland may have an inhibitory influence on mammary tumor growth in mice.

Endometrial polyps in postmenopausal women.

The malignancy risk of endometrial polyps in postmenopausal women was correlated with the presence or absence of abnormal uterine bleeding. Of 481 postmenopausal women who presented with endometrial polyps at diagnostic hysteroscopy between 2004 and 2007, 48.9% were asymptomatic and 51.1% had postmenopausal uterine bleeding. Transvaginal ultrasound revealed abnormal endometrial thickness in 60.0% vs. 57.7%, polyps in 37.9% vs. 32.9%, endometrial tumors in 1.3% vs. 0.8%, and submucosal myomas in 0.9% vs. 2.0% by the absence or presence of bleeding. Around three-fourth of the polyps were removed. Histopathologic diagnoses showed mucous polyps in 93.7 of asymptomatic women compared to 80.7% of those with bleeding, while endometrial tumors were only seen in those bleeding (7.2%). The malignancy risk within endometrial polyps in postmenopausal women varies with the presence of vaginal bleeding, and is minimal in asymptomatic women.

Potential impact of nonavalent HPV vaccine in the prevention of high-grade cervical lesions and cervical cancer in Portugal.

OBJECTIVE: To estimate the potential impact of the nonavalent HPV vaccine for high-grade cervical lesions and invasive cervical cancer (ICC) in Portugal. METHODS: The present secondary analysis used data collected in the CLEOPATRE II study on the prevalence of HPV 6/11/16/18/31/33/45/52/58 among female patients aged 20-88 years. The prevalence of HPV types in patients with cervical intraepithelial neoplasia (CIN) grades 2/3 and ICC was examined. RESULTS: Data were included from 582 patients. There were 177, 341, and 64 patients with CIN2, CIN3, and ICC, respectively, and 169 (95.5%), 339 (99.4%), and 62 (96.9) of them had HPV infections. Of patients with HPV infections, HPV 16, 18, 31, 33, 45, 52, and 58 infections were identified in 150 (88.8%), 329 (97.1%), and 60 (96.8%) patients with CIN2, CIN3, and ICC, respectively. HPV genotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58 were identified in 540 (94.7%) of the patients with HPV infections. CONCLUSION: The addition of the five HPV genotypes included in the nonavalent HPV vaccine (HPV 31/33/45/52/58) could result in the new HPV vaccine preventing 94.7% of CIN2/3 and ICC occurrences.

Hematogenic Dissemination of Triple-negative Versus Hormonal Receptor-positive Breast Cancer Cells.

The aim of this study was to characterize the hematogeneous spread, in vivo, of breast cancer (BC) cell lines that express hormonal receptors (HR) comparing with triple-negative (TN) BC, particularly considering the lung and liver. Female Balb/c nu nu mice (n=30) were injected with two breast cancer cell lines (MCF7 and HCC1806). Nuclear medicine imaging with Technetium ((99m)Tc)-hydroxymethylene diphosphonate ((99m)Tc-HMDP) and (99m)Tc-Hexakis 2-methoxy-2-methylpropylisonitrile (MIBI) were performed between the 7th and 8th weeks after injection. The histological metastatic foci were analyzed by morphometric and immunohistochemistry studies regarding estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (ERBB2) and cytokeratin (CK)-5/6. The mean area of lung metastasis in MCF7 cases was significantly higher (p=0.023), although the number of liver foci was higher in the HCC1806 group (p=0.006). Logistic regression revealed a potentiating model for liver metastasis with HCC1806 cells (odds ratio=16; p=0.03). The number and area of lung-metastatic foci were not predictive of liver dissemination. Lung metastasis study showed ER positivity in 57.1% of the MCF7 group, compared to 80% of the HCC1806 group. PR was positive in 42.9% of MCF7 cases and negative in 60% of HCC1806 cases. HR-positive cells developed massive lung metastization. TN cells seem to potentiate liver metastasis. ER, PR, ERBB2 and basal-like CK expression in metastases was not uniformly correlated with that of primary tumor cells.

Microdialysis: improving local chemotherapy in cancer using a mathematical model.

Although intratumoral chemotherapy administration has been evaluated in the past, its results have not been frequently comparable to those from systemic administration. We recently described microdialysis as a method for local chemotherapy administration with increasing effectiveness while reducing systemic toxicity. We present a mathematical model which supports the successful application of this procedure in optimizing the administered drug in different cases, using informatics tools and considering several parameters. We also review and discuss important aspects of cancer biology that should be taken into consideration in cancer chemotherapy, such as tumor heterogeneity, drug resistance and metastasis, and how this technique may be used to overcome any set-backs presented by these.

Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.

INTRODUCTION: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. METHODS: Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. RESULTS: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). CONCLUSION: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.