ß-hCG-induced mutant BRCA1 ignites drug resistance in susceptible breast tissue.

ß-hCG expression in breast cancer is highly controversial with reports supporting both protective and tumorigenic effects. It has also been reported that risk of breast cancer at an early age is increased with full-term pregnancies if a woman is a BRCA1 mutation carrier. We have already demonstrated that BRCA1-defective cells express high levels of ß-hCG and that when BRCA1 is restored, ß-hCG level is reduced. Also, BRCA1 can bind to the promoter and reduce the levels of ß-hCG. ß-hCG induces tumorigenicity in BRCA1-defective cells by directly binding to TGFBRII and induces TGFBRII-mediated cell proliferation. In this study, we analyzed the mechanism of action of ß-hCG on BRCA1 expression and its influence on drug sensitivity in breast cancer cells. We demonstrate that ß-hCG induces mutant BRCA1 protein expression in BRCA1 mutant cells; however, in BRCA1 wild-type cells, ß-hCG reduced wild-type BRCA1 protein expression. Transcriptionally, ß-hCG could induce Slug/LSD1-mediated repression of wild-type and mutant BRCA1 messenger RNA levels. However, ß-hCG induces HSP90-mediated stabilization of mutant BRCA1 and hence the overexpression of mutant BRCA1 protein, resulting in partial restoration of homologous recombination repair of damaged DNA. This contributes to drug resistance to HSP90 inhibitor 17AAG in BRCA1-defective cancer cells. A combination of HSP90 inhibitor and TGFBRII inhibitor has shown to sensitize ß-hCG expressing BRCA1-defective breast cancers to cell death. Targeting the ß-hCG-HSP90-TGFBRII axis could prove an effective treatment strategy for BRCA1-mutated breast tumors.

The implementation of an organised cervical screening programme in Poland: an analysis of the adherence to European guidelines.

BACKGROUND: Well-organised quality-controlled screening can substantially reduce the burden of cervical cancer (CC). European guidelines (EuG) for quality assurance in CC screening provide guidance on all aspects of an organised screening programme. Organised CC screening in Poland was introduced in 2007. The purpose of our study was to analyse: (i) adherence of the programme to EuG; (ii) programme process and performance indicators; (iii) impact of the programme on the incidence of and mortality from CC. METHODS: Available data on the policy, structure and functioning of the Polish programme were compared with the major points of the EuG. Data on the process, and available performance indicators were drawn from the screening database and other National Health Fund (NHF) systems. Joinpoint regression was used to assess changes in CC incidence and mortality trends. RESULTS: The Polish programme adheres partially to EuG in terms of policy and organisation. Only a limited set of performance indicators can be calculated due to screening database incompleteness or lack of linkage between existing databases. The screening database does not include opportunistic smears collected within NHF-reimbursed or private care. The organised programme coverage rate fluctuated from 21% to 27% between 2007-2013. In 2012 the coverage reached 35% after combining both organised and opportunistic smears reimbursed by the NHF. In 2012 the number of smears reimbursed by NHF was 60% higher in opportunistic than in organised screening with significant overlap. Data from the private sector are not recorded. Depending on years, 30-50% of women referred for colposcopy/biopsy because of abnormal Pap smears were managed within the programme. The age-standardised CC incidence and mortality dropped linearly between 1999 and 2011 without evidence of a period effect. CONCLUSIONS: The Polish organised cervical screening programme is only partially adherent to evidence-based EuG. Its implementation has not influenced the burden of CC in the country so far. Changes with special focus on increasing coverage, development of information systems and assessment of quality are required to increase programme adherence to EuG and to measure its effectiveness. Our findings may be useful to improve the Polish programme and those implemented or planned in other countries.

Challenges in starting organised screening programmes for cervical cancer in the new member states of the European Union.

Following the 2003 Recommendation of the Council of the European Union on cancer screening, equal access to organised cervical cancer screening is supposed to be ensured for all women at risk in all member states. However, the first IARC report on the implementation of the Council Recommendation suggests that a remarkable proportion of women in the new member states are not yet covered with the free Pap tests offered either in organised or opportunistic manners. Cervical cancer incidence and mortality rates in most of these countries are among the highest in Europe. The purpose of this paper is to identify some common challenges and make further proposals in organising and implementing quality-assured cervical cancer screening programmes in these countries. Based on the responses to a corresponding questionnaire, a summary on cervical cancer prevention policies was established for the seven new European Union member states, Czech Republic, Latvia, Lithuania, Poland, Romania, Slovakia and Slovenia, and two candidate states, Croatia and Serbia. In most of these countries there are a lot of challenges to overcome before achieving the level of preventive services as seen in Finland and the Netherlands nowadays.

Process performance of cervical screening programmes in Europe.

Standardised tables of aggregated data were collected from 15 European national or regional cervical screening programmes and key performance indicators computed as reported in European Union (EU) Guidelines, 2nd edition. Cytological results varied widely between countries both for the total proportion of abnormal tests (from 1.2% in Germany (Mecklenburg-Vorpommern) to 11.7% in Ireland-Midwest Region) and for their distribution by grade. Referral rates for repeat cytology (ranging from 2.9% of screened women in the Netherlands to 16.6% in Slovenia) or for colposcopy (ranging from 0.8% in Finland to 4.4% in Romania-Cluj) and the Positive Predictive Value (PPV) of colposcopic attendance (ranging from 8% in Romania-Cluj to 52% in Lithuania) were strongly influenced by management protocols, in particular for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. However, cytology-specific PPV also showed remarkable variability. The detection rate of CIN2+ histology ranged from <0.1% of screened women in Poland to >1% in England and Denmark. Low attendance for colposcopy after referral was observed in some east-European countries. These comparisons may be useful for improving the performance of cervical screening in general and more so if new screening technologies and vaccination for Human Papillomavirus are introduced. Overall, quality was better in countries that have operated organised programmes for a longer time, plausibly as a result of long-lasting monitoring and quality assurance activities. Therefore, the availability of these data, the first comparing European countries, and the increased number of countries that can provide such data (only five in 2004) represent progress. Nevertheless, there is a clear need to standardise the cytological and histological classifications used in screening, as well as data registration systems across Europe.

[Analysis of labour and perinatal complications in case of foetus weight over 4000 g]. / Analiza przebiegu porodów oraz powiklan okoloporodowych u noworodków z masa urodzeniowa przekraczajaca 4000 g.

UNLABELLED: The fetal macrosomia occurs in 3-15% pregnancies. It is recognized when foetus weight exceeds 4000 g in any period of pregnancy. Macrosomia can also be determined in case of foetus weight over 90 percentyl for the appropriate pregnancy period. The most detrimental foetal complications of macrosomia are: shoulder dystocia with Erb's brachial palsy, facial nerve palsy, clavicular and humeral bone fracture. The attempts in order to eliminate these complications lead to increase in the number of caesarean sections and labour inductions. Clinical examination and assessment of risk factors as well as ultrasonographic examination cannot exclude or confirm the possibility of macrosomia with sufficient specificity and sensitivity. On the other hand it is well known that delivery of macrosomic foetus is not always associated with perinatal complications. The aim of the study was to assess the risk of perinatal complication in foetuses with large birth weight. MATERIAL AND METHODS: In case-control study the data from medical records of 652 newborns with birth weight over 4000 g were analysed. Only single born at term foetuses in cephalic presentation were included into the analysis. RESULTS: The Erb's brachial palsy, clavicular bone fracture, shoulder dystocia and convulsions in newborn were significantly associated with excessive fetal weight. Shoulder dystocia, clavicular bone fracture and brachial palsy were more frequent in group of newborns with birth weight over 4500 g. The frequency of brachial dystocia and its complications (clavicular bone fracture and Erb's brachial palsy) were significantly connected with the use of VE. CONCLUSIONS: Significant increase in the frequency of perinatal complications in foetuses with birth weight over 4500 g indicates the necessity of considering caesarean section as a favourable mode of delivery.

[Survival of cervical cancer patients in selected regions of Poland in 1990-1996, in relation to some prognostic factors]. / Ocena przezyc chorych na raka szyjki macicy w wybranych rejonach Polski w latach 1990-1996 z uwzglednieniem niektórych czynników rokowniczych.

To evaluate whether cervical cancer patients in selected regions of Poland show similar 5-year survival rates and if they are different from European average and, also, to evaluate the effect of selected prognostic factors. The analysis based on a cohort of 1386 cervical cancer cases identified by population-based Cancer Registries collecting data from Kieleckie and Opolskie voivodships and from the City of Warsaw in 1990-96. These data become complete by adding information from medical records. The 5-year relative survival rates were calculated using the life tables method, and, a multivariant regression analysis was applied for evaluation of prognostic factors. The regions differed significantly in stage distribution (p<0.001), however, they were similar in age groups and histological diagnosis. The age-standardized relative 5-year overall survival rate was 52.2%, and was among lowest rates in Europe. The rate in Kieleckie was 60.7%; in Opolskie--43.3%, and in Warsaw--51.9%. The rates for Stage I in those regions were comparable at over 80%, but were different for Stage II and higher stages. The multivariant analysis showed a significant risk increase related to stage advancement (p<0.0001) as well as to the place of living in Opolskie (p=0.02) and to the adenocarcinoma diagnosis (p=0.05). However, the analysis did not confirm the effect of age of diagnosis as a prognostic factor. The overall, age-standardised 5-year relative survival rates of cervical cancer patients are one of the lowest in Europe, though diversified in the regions. They are almost satisfactory and close to European average in Kieleckie where prevention was effective, but poor in the other regions. The low survivals overall are basically due to the unsatisfactory proportion of the early stage of disease. The uneven survivals of patients with Stage II and higher stages of cancer in the selected regions of Poland suggest different standards of treatment.

Alterations in the expression of selected MHC antigens in premalignant lesions and squamous carcinomas of the uterine cervix.

BACKGROUND: The objective of the study was to determine whether there is a correlation between expression of selected major histocompatibility complex (MHC) antigens and the presence of carcinoma and premalignant lesions of the cervix. We also attempted to determine whether there is a correlation between expression of the selected MHC antigens in each grade of cervical intraepithelial neoplasia (CIN) and invasive carcinoma of the cervix. METHODS: Quantitative comparative analysis of MHC class I and class II expression between specimens of the uterine cervix was carried out. For detecting human leukocyte antigen (HLA) class I molecules, two primary antibodies were used, recognizing either epitopes of all free heavy chain class I molecules or epitopes of the HLA-Bw4 antigen. HLA class II antigens were detected by antibodies reacting with the alpha-chain of the HLA-DR molecule. An indirect immunoperoxidase technique was carried out using paraffin-embedded sections. The following groups of sections were formed: squamous metaplasia, CIN of different grades, and invasive carcinoma. The specimens were taken from women in whom routine histopathologic diagnosis of cervical lesions had been performed. RESULTS: A significant decrease in the mean number of stained cells showing expression of MHC class I antigens (HC 10 and Bw4) was found in the invasive cancer group of specimens. A decrease in Bw4 expression was also found in the CIN III group. The highest expression of the HLA-DR antigens was detected in the metaplastic epithelium compared to the other groups. In the dysplastic epithelium the expression of the HLA-DR antigens was increased in the highest grade of dysplasia (CIN III). Upregulation of HLA-DR expression was detected in invasive cancer specimens. CONCLUSIONS: Alterations in MHC expression are found in premalignant lesions and squamous carcinomas of the uterine cervix. Quantitative assessment with the use of an image analysis system is valuable in helping to discriminate staining patterns of HLA expression. Further studies are indicated to evaluate the prognostic value of the expression of selected MHC antigens.

[Postoperative verification of cervical intraepithelial neoplasia grade]. / Pooperacyjna ocena zaawansowania procesu sródnablonkowej neoplazji szyjki macicy.

UNLABELLED: Colposcopically directed punch biopsy and endocervical curettage is considered to be a "gold standard" in diagnosing premalignant lesions of the uterine cervix. However, in daily routine practice the CIN grade, assessed on the basis of colposcopically directed punch biopsy, sometimes differs from postoperative histopathological evaluation. Such a situation can influence the methods and outcomes of further treatment of women with premalignant lesions of the uterine cervix. OBJECTIVE: The comparison of histopathological diagnoses of punch biopsies to postoperative findings. MATERIAL AND METHODS: The accuracy of punch biopsies findings was evaluated in 104 women treated in the Gynecology Ward of the District Hospital in Kielce in the years 1996-2000. Women with cytological diagnosis of LGSIL and HGSIL were included to the study. Histopathological findings of colposcopically directed punch biopsies and endocervical curettage were compared to definitive diagnoses of postoperative material obtained by conization or hysterectomy. RESULTS: Discrepancies between the diagnosis of CIN grade, evaluated by colposcopically directed punch biopsies, and postoperative findings were detected in 37 cases (35.5%). Lower grade of CIN evaluated in biopsy was found in 23 cases (22.1%). Discrepancies in this group were found most often when colposcopy was unable to examine the entire lesion and positive endocervical specimen was obtained by curettage. In 12 (11.5%) cases when preoperative diagnosis showed CIN an early invasion was detected in postoperative material. CONCLUSIONS: Significant discrepancies were found between pre- and post-operative evaluation of CIN grade. Therefore in each case of LGSIL diagnosed in punch biopsy HGSIL should be ruled out. Expectant management of LGSIL lesions and ablative treatment of CIN should be performed only in centers with highly qualified medical staff experienced in colposcopy and cytology. It seems to be advisable to discriminate a group threatened with fast progression into CIN III or cancer among women with LGSIL (e.g. typing of high risk HPV, aneuploidy).