PSMD9 expression correlates with recurrence after radiotherapy in patients with cervical cancer.

In the current retrospective cohort study, the expression of the Proteasome 26S non-ATPase Subunit 9 (PSMD9) was investigated in 102 patients with cervical cancer. The rat homologue of PSMD9, Bridge-1, was identified as a binding protein of the transcription factors PDX-1 and E-12 via its PDZ-domain. The aim of the current study was to evaluate the prognostic or predictive value of PSMD9 expression as a biomarker for patients with cervical cancer. Tissue microarrays were constructed from formalin-fixed paraffin-embedded tissue specimens of cervical cancer and peritumoral stroma after hysterectomy and a Bridge-1 antibody was used to perform immunohistochemistry. The immunoreactions were analyzed using an immunoreactive score, which evaluated the number of positive cells as well as their intensity of PSMD9 expression. A misinterpretation of statistically significant results after multiple testing was controlled by the false discovery rate correction using the algorithm of Benjamini and Hochberg. All tumor tissues and almost all peritumoral stroma tissues expressed PSMD9. The PSMD9 expression in tumor tissues was significantly higher compared with the peritumoral stroma. PSMD9 expression correlated significantly with the expression of the proliferation marker MIB-1. Patients with stronger PSMD9 expression tended to exhibit a higher odds ratio for the recurrence of the disease in all patients (n=102) as well as in the subgroup of 47 patients having received a combined chemoradiotherapy following hysterectomy. In the group of 62 patients having that received radiotherapy following hysterectomy, which included the chemoradiotherapy patients, a higher PSMD9 expression significantly increased the odds for a recurrence to 1.983-fold even after FDR correction (P=0.0304). In conclusion, PSMD9 was indicated to be overexpressed in tumor tissues and associated with tumor cell proliferation. Therefore, PSMD9 may be useful as a tumor marker. Furthermore, increased PSMD9 overexpression may be used to predict resistance against radiation.

Anxiety in caregiving partners of breast cancer patients.

PURPOSE: The aim of the present study was to determine the levels of anxiety of partners of breast cancer patients and to evaluate the differences of anxiety levels between patients and partners according to the stage of treatment, age and education level. METHODS: 57 spouses or domestic partners of breast cancer patients and 148 breast cancer patients participated in this prospective cohort study and filled out the questionnaires including the Spielberger state-trait-anxiety-inventory, as well as questions based on stress-triggering procedures during breast cancer diagnosis and therapy. RESULTS: State anxiety levels of partners were highest in partners who accompanied their patients when presenting for examinations and operations and tumorboard decisions (Mean State-Scores 52, 45 and 46.5). Anxiety scores were lowest at the stage of ongoing chemotherapy or follow-up. The 25% quartile of partners with the highest state anxiety levels had a significantly higher educational level (p = 0.023). Young men aged 18-35 years showed the highest levels of both trait and state anxiety. Partners showed significantly higher levels of anxiety than the patients for anesthetic complications (p < 0.001), e.g., fear of not waking up from general anesthetic and postoperative pain (p < 0.001). Patients showed significantly higher levels of anxiety for hairloss (p < 0.001), weight gain during chemotherapy (p < 0.001) and postoperative scars (p = 0.027). CONCLUSION: Breast cancer patients are much more concerned about body image issues than their male partners. As these body image-associated concerns often arise from the fear of loosing attraction to their partner, these fears might be reduced by speaking about them openly. Partners are mostly concerned about surgery and anesthetic-related complications. Therefore, preoperative medical information to the partner is mandatory. Partners of breast cancer patients should be included in psycho-oncological support and medical briefings. Probably high anxiety levels of both partners and patients should be taken into account (due to younger age, lower educational level and procedures causing distress). These partners and patients should receive extra careful (clarification) counselling and (treatment support such as a psycho-oncologist) involvement of a psyco-oncologist.

Elaborations on Corallopyronin A as a Novel Treatment Strategy Against Genital Chlamydial Infections.

Ascending Chlamydia trachomatis infection causes functional damage to the fallopian tubes, which may lead to ectopic pregnancy and infertility in women. Treatment failures using the standard regimens of doxycycline and azithromycin have been observed. We tested the polyketide-derived α-pyrone antibiotic Corallopyronin A (CorA) that inhibits the bacterial DNA dependent RNA polymerase and has strong activity against various extracellular and some intracellular bacteria. Extensive testing in cell culture infection models and in an ex vivo human fallopian tube model under different oxygen concentrations was performed to assess the anti-chlamydial efficacy of CorA at physiological conditions. CorA showed high efficacy against C. trachomatis (MICN/H: 0.5 µg/mL for serovar D and L2), C. muridarum (MICN/H: 0.5 µg/mL), and C. pneumoniae (MICN/H: 1 µg/mL) under normoxic (N) and hypoxic (H) conditions. Recoverable inclusion forming units were significantly lower already at 0.25 µg/mL for all tested chlamydiae. CorA at a concentration of 1 µg/mL was also effective against already established C. trachomatis and C. pneumoniae infections (up to 24 h.p.i.) in epithelial cells, while efficacy against C. muridarum was limited to earlier time points. A preliminary study using a C. muridarum genital infection model revealed corresponding limitations in the efficacy. Importantly, in an ex vivo human fallopian tube model, the growth of C. trachomatis was significantly inhibited by CorA at concentrations of 1-2 µg/mL under normoxic and hypoxic conditions. The overall high efficacies of CorA against C. trachomatis in cell culture and an ex vivo human fallopian tube model under physiological oxygen concentrations qualifies this drug as a candidate that should be further investigated.

Treatment anxiety in breast cancer patients.

INTRODUCTION: The aim of the present study was to determine and evaluate the levels of anxiety of breast cancer patients according to the state of treatment, age and education level, as well as the anxiety potential of certain procedures during breast cancer treatment. METHOD: 148 breast cancer patients participated in this prospective cohort study and filled out the questionnaires including the Spielberger state-trait-anxiety-inventory, as well as questions based to stress triggering procedures during breast cancer therapy. The testing was accomplished with the Mann-Whitney U test, the significance level was set to 0.05. RESULTS: Patients who appeared for tumor board decision showed the highest state-anxiety levels (55.79 SD ± 18.73) followed by patients undergoing surgery (50.24 SD ± 13.84). Patients already undergoing chemotherapy had lower state-anxiety levels than the group of all other patients (p = 0.012). Women undergoing chemotherapy showed lower anxiety levels relating to many procedures of breast cancer treatment. The 25% quartile of patients with the highest levels in the trait score showed a significant poorer education level (p = 0.009). Age showed no statistical influence on the anxiety level of breast cancer patients.  CONCLUSION: Patients with probably high anxiety levels (younger age, low education level, and those appearing for frightening procedures) should receive extra careful clarification and treatment support such as a psycho-oncologist.

Microbiota-based analysis reveals specific bacterial traits and a novel strategy for the diagnosis of infectious infertility.

Tubal factor infertility (TFI) accounts for more than 30% of the cases of female infertility and mostly resides from an inflammatory process triggered by an infection. Clinical appearances largely differ, and very often infections are not recognized or remain completely asymptomatic over time. Here, we characterized the microbial pattern in females diagnosed with infectious infertility (ININF) in comparison to females with non-infectious infertility (nININF), female sex workers (FSW) and healthy controls (fertile). Females diagnosed with infectious infertility differed significantly in the seroprevalence of IgG antibodies against the C. trachomatis proteins MOMP, OMP2, CPAF and HSP60 when compared to fertile females. Microbiota analysis using 16S amplicon sequencing of cervical swabs revealed significant differences between ININF and fertile controls in the relative read count of Gardnerella (10.08% vs. 5.43%). Alpha diversity varies among groups, which are characterized by community state types including Lactobacillus-dominated communities in fertile females, an increase in diversity in all the other groups and Gardnerella-dominated communities occurring more often in ININF. While all single parameters did not allow predicting infections as the cause of infertility, including C. trachomatis IgG/IgA status together with 16S rRNA gene analysis of the ten most frequent taxa a total of 93.8% of the females were correctly classified. Further studies are needed to unravel the impact of the cervical microbiota in the pathogenesis of infectious infertility and its potential for identifying females at risk earlier in life.

Effects of Combined Treatment with Vitamin D and COX2 Inhibitors on Breast Cancer Cell Lines.

BACKGROUND: Vitamin D is known for its anticancer potential. Prostaglandin E2 (PGE2) is a proliferative and inflammation-activating agent. The production of PGE2 is dependent on the activity of cyclooxygenase-2 (COX2). A link between vitamin D and PGE2 metabolism was shown recently. MATERIALS AND METHODS: In MDA-MB-231 and MCF-7 breast cancer cell lines, we investigated the influence of calcitriol and the COX2 inhibitor celecoxib on cell growth via the MTT test, as well as on the protein and mRNA expression of COX2 using western blot and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The proliferation of MCF-7 and MDA-MB-231 was inhibited by both calcitriol and the COX2 inhibitor celecoxib and even more strongly by their combination. Moreover, calcitriol inhibited COX2 protein expression in MDA-MB-231 cells, as well as COX2 mRNA expression in both cell lines. CONCLUSION: The combination of calcitriol and celecoxib demonstrated a synergistic growth-inhibitory effect in breast cancer cell lines.

Claudin-1 expression in cervical cancer.

Claudin-1 is a tight junction protein that has been demonstrated to be involved in tumorigenesis and tumor progression in various types of solid tumors. In the present study, the protein expression of claudin-1 in squamous cervical cancer tissues obtained from 106 patients was analyzed by immunohistochemistry. In addition, the grade of claudin-1 expression was analyzed for associations with certain clinicopathological parameters. A significant overexpression of claudin-1 was detected in the tumor cells, when compared with that in the peritumoral stroma. There was no significant association between claudin-1 expression and FIGO stage, tumor size, grading or the appearance of distant metastases. Cervical cancer patients scoring positive for claudin-1 protein expression tended to exhibit more lymph node metastasis (28.3%), compared with claudin-1-negative patients (7.1%). Regarding overall survival, the results of the present study suggest a better prognosis for claudin-1-negative patients. In order to elucidate whether claudin-1 overexpression has a significant prognostic impact on squamous cervical cancer, further studies are required.

Fetal cephaloceles: prenatal diagnosis and course of pregnancy in 65 consecutive cases.

PURPOSE: To scrutinize the characteristics of all cases with antenatally established diagnosis of cephalocele in two tertiary referral centers. METHODS: We retrospectively reviewed 65 cases diagnosed with cephaloceles and tabulated sonographic findings and autopsy recordings as well as medical charts of all survivors in terms of clinical outcome. RESULTS: The case notes of 65 fetuses were available for final analysis. Gestational age (GA) at diagnosis ranged from 10.4 to 38.1 weeks. Of our cohort, 53/65 cases (80%) had occipital protrusions, 10 (15%) were found to have frontal lesions, and another two had parietal cephaloceles. A total of 52 pregnancies were terminated or resulted in intrauterine fetal demise (78%). In 18 cases (11%), the cephalocele was part of underlying syndromic disorders (e.g., Meckel-Gruber syndrome). Thirteen pregnancies were continued until term, out of which all affected individuals were live-born. Neurosurgical intervention was prompted within the first 7 months postnatally. CONCLUSIONS: In general, the outcome of fetuses with cephaloceles is rather poor as four out of five pregnancies were terminated. Postnatal outcome of all survivors in our cohort was rather determined by localization of the cele and more important by the presence and severity of concomitant malformations than the extent of the lesion.

Expression of cyclooxygenase-2 in cervical cancer is associated with lymphovascular invasion.

Cyclooxygenase-2 (COX-2) is associated with carcinogenesis and tumor progression. The current study analyzed the effect of COX-2 expression in patients with invasive squamous cervical cancer. Tissue samples from 123 cervical cancer patients were collected for a retrospective analysis using immunohistochemistry (IHC) with an antibody against COX-2. The clinical and survival data of the patients were analyzed. Positive staining for COX-2 (defined as an immunoreactivity score of ≥4) was detected in 28 patients (23%), with significantly higher percentages of staining in tumor cells compared with peritumoral stroma cells (P<0.001). COX-2 expression was significantly associated with lymphovascular space invasion (LVSI; P=0.017). The association of COX-2 expression with LVSI suggests a possible effect of COX-2 on tumor progression in cervical cancer. Further studies including larger patient collectives are required in order to perform analyses of clinical subgroups and patient survival.

Trefoil factor 3 expression in epithelial ovarian cancer exerts a minor effect on clinicopathological parameters.

The role of trefoil factor 3 (intestinal) (TFF3) has been analyzed in numerous cancers, such as breast and gastrointestinal cancer, and has been associated with poor prognosis. However, the role of TFF3 in ovarian cancers is not clear. Expression analysis of TFF3 in 91 ovarian cancer patients was performed by immunohistochemistry of primary paraffin-embedded tumor samples. The results were scored according to staining intensity and percentage of positive tumor cells resulting in an immune-reactive score (IRS) of 0-12. These results were correlated with clinicopathological characteristics and survival. TFF3 expression in our patient cohort exhibited a tendency towards improved overall and progression-free survival (PFS). In TFF3-positive serous and high-grade serous ovarian cancers, the median PFS was 27.6 months [95% confidence interval (CI): 0-55.7] vs. 15.2 months in TFF3-negative tumors (95% CI: 13.8-16.6) (P=0.183). The median overall survival was 53.9 months in TFF3-positive tumors (95% CI: Non-applicable) vs. 44.4 months in TFF3-negative cases (95% CI: 30.5-58.3) (P=0.36). TFF3 negativity was significantly associated with higher tumor grade (P=0.05). Based on our results, further studies are required in order to elucidate whether survival and chemosensitivity are affected by TFF3 expression in ovarian cancer.

Management of Very Early-onset Fetal Growth Restriction: Results from 92 Consecutive Cases.

AIM: To evaluate management of early-onset intrauterine growth restriction (IUGR) and to define outcome according to obstetric setting. PATIENTS AND METHODS: During an 11-year period (2000-2011), data of patients presenting with IUGR and preterm delivery of less than 30 weeks of gestation at a tertiary perinatal center were retrospectively reviewed. RESULTS: A total of 92 pregnancies were investigated. Delivery was indicated for fetal reasons in 38 out of 92 patients. Sixteen children of our cohort died within one year post partum, out of which eight had suffered from severe early-onset IUGR causing iatrogenic preterm delivery. Concerning the fetal outcome, gestational age at delivery and antenatal exposure to corticosteroids were found to be crucial. CONCLUSION: In some cases, respiratory distress syndrome prophylaxis and a "wait and see" approach to management in favor of a prolongation of the pregnancy might be favorable. Randomized prospective trials in early-onset IUGR with threatened preterm deliveries are needed in order to define guidelines for an individually tailored management of early-onset preterm infants.

Combined treatment of breast cancer cell lines with vitamin D and COX-2 inhibitors.

BACKGROUND: Vitamin D is known for its anti-cancerogenous potential. Prostaglandin E2 (PGE2) is a proliferation and inflammation activating agent. The production of PGE2 is dependent on the activity of cyclooxygenase-2 (COX-2). A link between vitamin D and PGE2 metabolism was recently shown. MATERIALS AND METHODS: In MDA-MB-231 and MCF-7 breast cancer cell lines we investigated the influence of calcitriol and the COX-2 inhibitor celecoxib regarding cell growth via MTT test, as well as on the protein and mRNA expression of COX-2 using western blot and qRT-PCR. RESULTS: The proliferation of MCF-7 and MDA-MB-231 was inhibited by both calcitriol and the COX-2 inhibitor celecoxib and even stronger by their combination. Moreover, calcitriol inhibited the COX-2 protein expression in MDA-MB-231, as well as the COX-2 mRNA expression in both cell lines. CONCLUSION: The combination of calcitriol and celecoxib demonstrated a cooperative growth-inhibiting effect in breast cancer cell lines.

Does maternal underweight prior to conception influence pregnancy risks and outcome?

AIM: Data analyzing risks during pregnancy and neonatal outcome in Caucasian women with pre-conceptional underweight are scarce. PATIENTS AND METHODS: We conducted a retrospective cohort study in Northern Germany comparing pregnancy risks and neonatal outcomes in nulliparous women with either pre-conceptional underweight or normal weight. RESULTS: The data of 3,854 nulliparous women with either underweight (n = 243; BMI ≤ 18.5 kg/m(2)) or normal weight (n = 3611; BMI 18.5-24.9 kg/m(2)) were screened. The risks for preterm birth (23.3 vs. 18.6%; p = 0.004) and neonatal underweight were significantly higher in women with underweight prior to conception (p < 0.0001). The risk for secondary caesarean sections was significantly lower in underweight patients. CONCLUSION: To our knowledge, the present retrospective cohort study constitutes the largest sub-group analysis on delivery and maternal and neonatal outcome in pre-conceptionally underweight mothers. There are significantly more preterm deliveries in underweight mothers, while maternal outcome and birth-associated trauma (lacerations, caesarean section) is not disadvantageously influenced by maternal underweight. Further investigations are required in order to specify nutritional deficits in underweight pregnant women and to optimize medication in cases where nutritional balance cannot be achieved in order to improve the neonatal status at birth.

The role of lymphadenectomy in uterine sarcoma: a clinical practical approach based on retrospective analysis.

BACKGROUND: Uterine sarcomas are rare, highly aggressive tumors with an unfavorable prognosis. Only limited data on treatment and outcome are available and the role of lymphadenectomy is controversial for this particular tumor type. PATIENTS AND METHODS: By performing a retrospective analysis, through clinical practice, we analyzed the impact of lymphadenectomy on patient outcome. RESULTS: Out of 52 patients, 48 women underwent surgical treatment. Among those, lymphadenectomy was performed in 58%. 10% underwent pelvic and paraaortic lymphadenectomy and 48% underwent pelvic lymphadenectomy alone. CONCLUSION: In our cohort, surgeons tended to perform paraaortic-plus-pelvic or pelvic-alone lymphadenectomy irrespective of the presence or absence of enlarged lymph nodes. Patients who underwent lymphadenectomy showed a better survival. This observation might indicate a potential role for systematic lymphadenectomy in the surgical treatment of uterine sarcoma. We review on clinical operative decisions, critically with regard to current evidence.

Hybrid approach of retractor-based and conventional laparoscopy enabling minimally invasive hysterectomy in a morbidly obese patient: case report and review of the literature.

Minimally invasive hysterectomy in obese patients may be limited by laparoscopic sight on the one hand and by intraoperative complications related to reduced ventilation due to pneumoperitoneum on the other. Retractor-based laparoscopy offers an operative technique reducing anesthesia risks. We report the case of laparoscopic hysterectomy in an obese patient of short stature. Laparoscopic supracervical hysterectomy was performed by a hybrid approach of a retractor system exerting its effects on lifting the abdominal wall through gravity and conventional laparoscopy, thus bypassing the adverse effects of pneumoperitoneum on ventilation.

Therapeutic drugs in the treatment of symptomatic uterine fibroids.

INTRODUCTION: The therapy of symptomatic uterine fibroids is based on surgery in the majority of cases. Conservative medical treatment in cases of contraindication against operative treatment, bleeding control or preoperative down-sizing of the fibroids is classically based on sex steroid depletion by gonadotropin-releasing hormone (GnRH) agonist administration for a prolonged period. However, this approach is associated with often severe climacteric side effects and fibroids quickly relapse after treatment cessation. Furthermore, the achievement of menstrual bleeding control has been tried by administration of combined oral contraceptives, progestins or the levonorgestrel-releasing intrauterine device. These approaches, however, are not associated with a significant reduction in fibroid volume. AREAS COVERED: With the introduction of Ulipristal acetate (UPA), a new selective progesterone receptor modulator (SPRM) is now licensed for the preoperative treatment of fibroids. The administration should be limited to 3 months. UPA induces amenorrhea within a relatively short term of - on average - 7 days and may thus reduce fibroid-induced anemia. Furthermore, a significant reduction of the fibroid volume persisting after cessation of the treatment could be demonstrated for UPA. Herein, a review of the current therapeutic options for conservative and preoperative medical fibroid treatment is given and the clinical utility of UPA is outlined. EXPERT OPINION: In contrast to precedent myoma medication, volume reduction of the fibroids persists several months after cessation of UPA-administration. UPA optimizes operative conditions and thus the postoperative outcome by reducing anemia and down-sizing of fibroids.

Influence of acetic acid on a pap smear of dysplastic lesion.

BACKGROUND: Cervical cancer prevention is performed by taking Pap smears. The correct execution of the smear is crucial as an inadequate smear might result in underdiagnosis. The second means of cervical cancer prevention is visual inspection of the cervix uteri with acetic acid, while often both methods are combined. We investigated whether the application of acetic acid compromises the Pap smear. PATIENTS AND METHODS: A total of 100 patients with dysplasia were prospectively included; Pap smears were obtained before and after the application of acetic acid. RESULTS: We observed an alteration of the result of the Pap smear after acetic acid application in 41%. However, these alterations did not result in a dysplastic case being classed as a normal smear or vice versa. CONCLUSION: The application of acetic acid to the transformation zone of the cervix uteri may enhance changes of the Pap smear in dysplasia, however, the changes affect subgroups of dysplasia and thus do not change therapeutic management.

Influence of calcitriol on prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cell lines.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a potential molecular prognostic factor for breast cancer, and calcitriol [1,25(OH)(2)D(3)], the biologically active form of vitamin D, is a promising target in breast cancer therapy. MATERIALS AND METHODS: The influence of calcitriol on the proliferation and the effects of calcitriol on the expression of prostaglandin- and vitamin D-metabolising enzymes were examined in benign and malignant breast cells. RESULTS: Calcitriol inhibited the proliferation of MCF-10F and MCF-7 cells but not of invasive MDA-MB-231 cells and reduced the expression of COX-2 and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in the benign breast cell line MCF-10F. Furthermore, dysregulation in vitamin D-metabolising proteins was detected, especially in MDA-MB-231 cells. CONCLUSION: These results suggest dysregulation of vitamin D metabolism and a lack of a possible influence of calcitriol on the metabolism of prostaglandins in the malignant breast cell lines.

Expression of prostaglandin- and vitamin D-metabolising enzymes in benign and malignant breast cells.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a crucial role in prognosis of malignancy and has been associated with carcinogenesis, particularly neoangiogenesis and tumor progression. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is described as a tumour suppressor in cancer. The antiproliferative effects of calcitriol [1,25(OH)(2)D(3)] mediated via the vitamin D receptor (VDR) render vitamin D a promising target in breast cancer therapy. MATERIALS AND METHODS: The expression of prostaglandin (PG)-metabolizing enzymes, vitamin D-metabolising enzymes and VDR were determined in benign and malignant breast cell lines using western blot analysis. RESULTS: We detected an inverse correlation between the two types of metabolism, a reduced VDR expression in the malignant breast cell lines, and therefore an insufficient induction of 24-hydroxylase in the malignant cells. CONCLUSION: We suggest the possibility of dysregulation of vitamin D-metabolizing enzymes in malignant breast cell lines.