Markus Valter

Cisplatin, doxorubicin and paclitaxel induce mdr1 gene transcription in ovarian cancer cell lines

The clinical observation of the multidrug resistance (MDR) phenotype is often associated with overexpression of the mdrl gene, in particular with respect to ovarian cancer. However, until now the mdrl-inducing potential of commonly used antineoplastics has been only incompletely explored. We performed short-term cultures of six ovarian cancer cell lines (MZOV4, EF027, SKOV3, OAW42, OTN14, MZOV20) exposed to either blank medium or cisplatin, doxorubicin or paclitaxel at concentrations related to the clinically achievable plasma peak concentration. A highly specific quantitative real-time RT-PCR was used to detect the Mdr1 transcripts. Mdrl mRNA contents were calibrated in relation to coamplified GAPDH mRNA. Mdrl mRNA was detectable in each cell line. In 13 out of 18 assays (72%) the specific anticancer drug being tested induced mdr1 transcription. No decrease in mdr1 mRNA concentration was observed. Our data suggest that mdr1 induction by antineoplastics is one of the reasons for failure of ovarian cancer therapy but may vary individually.

The V109G Polymorphism of the p27 Gene CDKN1B Indicates a Worse Outcome in Node-Negative Breast Cancer Patients

Although p27 plays a central role in cell cycle regulation, its role in breast cancer prognosis is controversial. Furthermore, the p27 gene CDKN1B carries a polymorphism with unknown functional relevance. This study was designed to evaluate p27 expression and p27 genotyping with respect to early breast cancer prognosis. 279 patients with infiltrating metastasis-free breast cancer were included in this study. p27 expression was determined in tumor tissue specimens from 261 patients by immunohistochemistry. From 108 patients, the CDKN1B genotype was examined by PCR and subsequent direct sequencing. 55.2% of the tumors were considered p27 positive. p27 expression did not correlate with any of the established parameters except for nodal involvement but significantly correlated to prolonged disease-free survival. In 35% of the tumors analyzed, the CDKN1B gene showed a polymorphism at codon 109 (V109G). The V109G polymorphism correlated with greater nodal involvement. In the node-negative subgroup, V109G correlated significantly with a shortened disease-free survival. In conclusion, the determination of the CDKN1B genotype might be a powerful tool for the prognosis of patients with early breast cancer.

Time to progression is dependent on the expression of the tumour suppressor PTEN in ovarian cancer patients

Background Quantitative analyses of PTEN expression of ovarian cancer tissues were performed in this study. PTEN expression was investigated in terms of each patients progression‐free interval to indicate the role of PTEN in the generation of platinum refractory tumours.

Prevalence and risk factors for oral human papillomavirus infection in 129 women screened for cervical HPV infection

BACKGROUND Oncogenic human papillomaviruses (HPV) are known to be associated with carcinomas of the uterine cervix. Furthermore, current studies have shown that HPV-infection is also associated with a subtype of oropharyngeal cancers. In general, a sexual transmission of the viruses has been shown by numerous studies in the genital lesions. However, there are unknown factors regarding the prevalence and transmission of HPV in the oropharynx. The aim of this study was to evaluate HPV prevalence in the oropharynx in female participants with and without genital HPV infection. In addition, we analyzed risk factors for an oropharyngeal colonization with HPV in their sexual partners, too. METHODS 129 Female participants were tested for presence of HPV-DNA by oral lavage, brush cytology of the tonsils and of the cervix. In addition, 15 male partners of these patients were included in the study. HPV-DNA was detected by PCR (polymerase chain reaction) amplification. For HPV-genotyping, PCR products were hybridized with type-specific digoxigenin-labeled oligonucleotide probes and discriminated into 14 high risk (HR) and 6 low risk (LR)-HPV types. The 129 female and 15 male participants were interviewed by a standardized questionnaire for socioeconomic details, drinking, smoking and sexual behaviours. RESULTS 59 (45.7%) Female participants were negative for a genital HPV-infection. Of these women, 3 (5.1%) showed a positive HPV-PCR result (HR and LR) in the oropharynx. 70 (54.3%) Female participants were positive for a genital HPV infection. In this group, 4 (5.7%) had a positive HPV-detection (HR and LR) in the oral cavity and oropharynx. Female participants with cervical HPV-infection had no higher risk for HPV-detection in the oropharynx (not significant). The analysis of sexual risk factors revealed no specific risk factor for an oral HPV-infection. CONCLUSION A correlation between cervical and oral colonization by HPV could not be demonstrated in our small cohort. Our limited data suggest that sexual transmission of HPV from the cervix uteri to the oropharynx is a rare and unlikely event.

High Apoptotic Index Correlates to p21 and p27 Expression Indicating a Favorable Outcome of Primary Breast Cancer Patients, but Lacking Prognostic Significance in Multivariate Analysis

This study was performed in order to investigate the role of the apoptotic index (AI) as a prediction parameter for the prognosis of patients with primary breast cancer. AI was determined by DNA fragmentation on 298 primary breast cancer samples and compared to clinically established breast cancer parameters. Additionally, we determined the expression of functional parameters including proliferating cell nuclear antigen, p21waf and p27kip by immunohistochemistry. The mean AI was found to be 11.9% (range, 0–90%). 189 tumors (63.4%) were negative for apoptosis, while 109 tissue samples (36.6%) were apoptotic with >5% positive cells. Using univariate analysis (χ2 test), the AI did not show any significant correlation to one of the established prognostic parameters of primary breast cancer (p > 0.05). In contrast, we found a significant positive correlation to the expression of the cell cycle inhibitors p21waf (p = 0.04) and p27kip (p = 0.024). During the clinical follow-up (median observation time for disease-free survival 87 months), several clinically established prognostic parameters including menopausal status, nodal status, tumor size, tumor grade, and hormone receptor expression could be confirmed and were analyzed with respect to the AI in the tumor. Furthermore, AI displayed a significant positive correlation to disease-free survival using Kaplan-Meier survival analysis (log-rank test, p = 0.04). However, AI lost its prognostic significance in multivariate analysis based on the Cox proportional hazard model (relative risk 0.8, confidence interval 0.52–1.33, p = 0.44). Our data indicate that high apoptotic rates in cancer tissues are indicative of a favorable patient outcome. However, the AI was not an independent factor. The study provides indirect evidence that this process may involve cell cycle inhibitors physiologically.

Experimental studies on the tensile properties of human umbilical cords

When tried in court, mothers accused of neonaticide may claim that the umbilical cord just broke during birth and the newborn child bled to death accordingly. To evaluate the possibility of a breakage of the umbilical cord is the goal of this work. Therefore 25 umbilical cords from neonates of both sexes born at term were stretched using an electrically operated material testing machine and the energy necessary to break them was measured. This experimental set-up equals a static strain, not a dynamic one. The maximum force endured (F max) ranged from 37.24 N to 150.04 N. The average force endured was 79.87 N with a standard deviation of 27.39. The elongation at break varied from 13.24% to a maximum of 119.93%. We found no relationship between the force endured and any of the following parameters: birth weight, pH of the venous umbilical blood, diameter of cord, free length under testing, duration of pregnancy or the mothers age. We performed a literature research and tried to define the circumstances in which a break is more likely to occur, these being malformations, entanglement or disease, e.g. inflammation.

Optical coherence tomography: A potential tool to predict premature rupture of fetal membranes

A fundamental question addressed in this study was the feasibility of preterm birth prediction based on a noncontact investigation of fetal membranes in situ. Although the phenomena of preterm birth and the premature rupture of the fetal membrane are well known, currently, there are no diagnostic tools for their prediction. The aim of this study was to assess whether optical coherence tomography could be used for clinical investigations of high-risk pregnancies. The thickness of fetal membranes was measured in parallel by optical coherence tomography and histological techniques for the following types of birth: normal births, preterm births without premature ruptures and births at full term with premature rupture of membrane. Our study revealed that the membrane thickness correlates with the birth type. Normal births membranes were statistically significantly thicker than those belonging to the other two groups. Thus, in spite of almost equal duration of gestation of the normal births and the births at full term with premature rupture, the corresponding membrane thicknesses differed. This difference is possibly related to previously reported water accumulation in the membranes. The optical coherence tomography results were encouraging, suggesting that this technology could be used in future to predict and distinguish between different kinds of births.

Chemopersistent early recurrence in the perineal tear scar of an intrapartally diagnosed cervical cancer.

BACKGROUND Cervical cancer is the most frequent cancer occurring in pregnancy. Apart from some general recommendations, there is no standardized consensus for the management of this cancer during pregnancy. Individual case reports do exist on intrapartal cancer diagnosis and risks. CASE We describe the case of an early recurrence in the perineal tear scar of an intrapartally diagnosed cervical cancer, which had developed despite combined neoadjuvant and adjuvant chemotherapy. CONCLUSIONS Although iatrogenic tumor cell spreading in the vagina is rare, this oncological risk is easy to avoid. It should be considered in the peripartal management of patients suffering from cervical cancer. Our case report underlines the limits of chemotherapy in the treatment of tumor residue and points out the problem of cervical cancer cell spreading during invasive procedures.

Implantation Despite an Extensive Endometrial Defect after Hysteroscopic Resection of Symptom-Free Residual Trophoblastic Tissue 15 Months after Cesarean Section

Successful implantation occurred after embryo transfer in the presence of an extensive endometrial defect after hysteroscopic resection of residual trophoblastic tissue 15 months after cesarean section. At the end of hysteroscopic surgery the anterior uterine wall seemed smooth, although ultimately no endometrium was left in that part and in parts of the fundus. Thus implantation is possible even with extensive endometrial defects. Interesting facts in this case were, first, the long symptom-free period with residual trophoblastic tissue in the uterus, and, second, successful implantation, pregnancy, and delivery despite at least 30% of endometrial surface being irreversibly destroyed. We suggest hysteroscopic resection as the method of choice for exact and minimally traumatic removal of especially older residual trophoblastic tissue.