Molecular dynamics identifies semi-rigid domains in the PD-1 checkpoint receptor bound to its natural ligand PD-L1.

Cells in danger of being erroneously attacked by leucocytes express PD-L1 on their surface. These cells activate PD-1 on attacking leucocytes and send them to death, thus curbing erroneous, autoimmune attack. Unfortunately, cancer cells exploit this mechanism: By expressing PD-L1, they guard themselves against leucocyte attack and thereby evade immune clearance. Checkpoint inhibitors are drugs which re-enable immune clearance of cancer cells by blocking the binding of PD-L1 to PD-1 receptors. It is therefore of utmost interest to investigate these binding mechanisms. We use three 600 ns all-atom molecular dynamics simulations to scrutinize molecular motions of PD-1 with its binding partner, the natural ligand PD-L1. Usually, atomic motion patterns are evaluated against whole molecules as a reference, disregarding that such a reference is a dynamic entity by itself, thus degrading stability of the reference. As a remedy, we identify semi-rigid domains, lending themselves as more stable and reliable reference frames against which even minute differences in molecular motion can be quantified precisely. We propose an unsupervised three-step procedure. In previous work of our group and others, minute differences in motion patterns proved decisive for differences in function. Here, several highly reliable frames of reference are established for future investigations based on molecular motion.

Sexual Function in Postmenopausal Women With Symptomatic Pelvic Organ Prolapse Treated Either with Locally Applied Estrogen or Placebo: Results of a Double-Masked, Placebo-Controlled, Multicenter Trial.

BACKGROUND: Local estrogen therapy (LET) has beneficial effects on genitourinary atrophy; however it is currently unclear if LET improves sexual function in postmenopausal women with pelvic organ prolapse (POP). AIM: To evaluate if LET vs placebo results in an improved sexual function in postmenopausal women with symptomatic POP. METHODS: We performed a secondary analysis of sexual outcomes of a previous randomized controlled trial comparing LET and placebo in 120 postmenopausal women (60/group) with symptomatic POP stage ≥3 and planned prolapse surgery. Women were randomly assigned to receive local estrogen or placebo cream 6 weeks preoperatively. The effect of therapy vs placebo was assessed with ANOVA with interaction effect of time*group and a multivariable linear regression model was built to assess the impact of different variables on sexual function before therapy. OUTCOMES: We evaluated the sexual function score in sexually active women of our study population using the German Pelvic Floor Questionnaire at recruitment time and again after 6 weeks of treatment. RESULTS: Among 120 randomized women, 66 sexually active women remained for final analysis. There was no significant difference in the change of the sexual function score over time between the treatment groups (difference in changes in score from baseline to 6 weeks for Estrogen group vs control group was -0.110 with 95% CI -0.364 to 0.144) Multivariable analysis showed that no independent risk factor for unsatisfying sexual function score could be identified. CLINICAL IMPLICATIONS: Based on our results, LET has no beneficial effect on sexual function in postmenopausal women with POP. STRENGTHS AND LIMITATIONS: Main strength of our study lies in the study design and in the use of a condition- specific questionnaire. As this is a secondary analysis, this study may be insufficiently powered to identify differences in sexual data between groups. CONCLUSION: LET had no impact on female sexuality in postmenopausal women with POP. Marschalek M-L, Bodner K, Kimberger O, et al. Sexual Function in Postmenopausal Women With Symptomatic Pelvic Organ Prolapse Treated Either with Locally Applied Estrogen or Placebo: Results of a Double-Masked, Placebo-Controlled, Multicenter Trial. J Sex Med 2022;19:1124-1130.

Decision Theory versus Conventional Statistics for Personalized Therapy of Breast Cancer.

Estrogen and progesterone receptors being present or not represents one of the most important biomarkers for therapy selection in breast cancer patients. Conventional measurement by immunohistochemistry (IHC) involves errors, and numerous attempts have been made to increase precision by additional information from gene expression. This raises the question of how to fuse information, in particular, if there is disagreement. It is the primary domain of Dempster-Shafer decision theory (DST) to deal with contradicting evidence on the same item (here: receptor status), obtained through different techniques. DST is widely used in technical settings, such as self-driving cars and aviation, and is also promising to deliver significant advantages in medicine. Using data from breast cancer patients already presented in previous work, we focus on comparing DST with classical statistics in this work, to pave the way for its application in medicine. First, we explain how DST not only considers probabilities (a single number per sample), but also incorporates uncertainty in a concept of 'evidence' (two numbers per sample). This allows for very powerful displays of patient data in so-called ternary plots, a novel and crucial advantage for medical interpretation. Results are obtained according to conventional statistics (ODDS) and, in parallel, according to DST. Agreement and differences are evaluated, and the particular merits of DST discussed. The presented application demonstrates how decision theory introduces new levels of confidence in diagnoses derived from medical data.

Clinical risk factors for recurrence of pelvic organ prolapse after primary native tissue prolapse repair.

OBJECTIVE: To define potential risk factors for recurrence of prolapse. METHODS: This short report included all women who presented with recurrence of prolapse as well as without any recurrence signs after a vaginal approach of native tissue prolapse repair at an urogynecological center in Austria. RESULTS: A total of 124 recurrence cases and 64 women with no signs of recurrence after their index prolapse surgery were included. Multivariate analysis identified advanced preoperative POP­Q stage (pelvic organ prolapse-quantification) as an independent risk factor for postoperative recurrence of prolapse (p = 0.045). CONCLUSION: Initial proper preoperative counseling is of particular importance to modulate patients' expectations after prolapse surgery.

Wide Variation in Post-Void Residual Management after Urogynecologic Surgery: A Survey of Urogynecologists' Practices.

To date there is no standardized regimen or evidence-based practical guideline concerning post-void residual (PVR) measurement after urogynecologic surgeries. This survey aimed to evaluate current practice patterns and the approach taken among urogynecologists surrounding PVR measurement. An online survey was sent to members of several urogynecologic societies assessing pre- and postoperative management of patients undergoing urogynecologic surgery. A total of 204 urogynecologists from 21 countries participated in the survey. The vast majority of urogynecologists perform some kind of voiding trial to assess voiding function postoperatively. The cut-off values to perform catheterization, the methods of measurement, and the number of successfully passed voiding showed strong differences. Only 34.4% of the respondents consider routine PVR measurement after urogynecologic surgery to be evidence-based. PVR measurement after urogynecologic surgeries is widely performed and if pathological, it almost always provokes invasive treatment. However, there is a wide variation of implemented strategies, methods, and cut-off values. Scientific societies are challenged to devise a standardized regimen based on evidence for the management of urinary retention after urogynecologic surgery.

Gene Expression-Based Prediction of Neoadjuvant Chemotherapy Response in Early Breast Cancer: Results of the Prospective Multicenter EXPRESSION Trial.

PURPOSE: Expression-based classifiers to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) are not routinely used in the clinic. We aimed to build and validate a classifier for pCR after NACT. PATIENTS AND METHODS: We performed a prospective multicenter study (EXPRESSION) including 114 patients treated with anthracycline/taxane-based NACT. Pretreatment core needle biopsies from 91 patients were used for gene expression analysis and classifier construction, followed by validation in five external cohorts (n = 619). RESULTS: A 20-gene classifier established in the EXPRESSION cohort using a Youden index-based cut-off point predicted pCR in the validation cohorts with an accuracy, AUC, negative predictive value (NPV), positive predictive value, sensitivity, and specificity of 0.811, 0.768, 0.829, 0.587, 0.216, and 0.962, respectively. Alternatively, aiming for a high NPV by defining the cut-off point for classification based on the complete responder with the lowest predicted probability of pCR in the EXPRESSION cohort led to an NPV of 0.960 upon external validation. With this extreme-low cut-off point, a recommendation to not treat with anthracycline/taxane-based NACT would be possible for 121 of 619 unselected patients (19.5%) and 112 of 322 patients with luminal breast cancer (34.8%). The analysis of the molecular subtypes showed that the identification of patients who do not achieve a pCR by the 20-gene classifier was particularly relevant in luminal breast cancer. CONCLUSIONS: The novel 20-gene classifier reliably identifies patients who do not achieve a pCR in about one third of luminal breast cancers in both the EXPRESSION and combined validation cohorts.

Decision theory for precision therapy of breast cancer.

Correctly estimating the hormone receptor status for estrogen (ER) and progesterone (PGR) is crucial for precision therapy of breast cancer. It is known that conventional diagnostics (immunohistochemistry, IHC) yields a significant rate of wrongly diagnosed receptor status. Here we demonstrate how Dempster Shafer decision Theory (DST) enhances diagnostic precision by adding information from gene expression. We downloaded data of 3753 breast cancer patients from Gene Expression Omnibus. Information from IHC and gene expression was fused according to DST, and the clinical criterion for receptor positivity was re-modelled along DST. Receptor status predicted according to DST was compared with conventional assessment via IHC and gene-expression, and deviations were flagged as questionable. The survival of questionable cases turned out significantly worse (Kaplan Meier p < 1%) than for patients with receptor status confirmed by DST, indicating a substantial enhancement of diagnostic precision via DST. This study is not only relevant for precision medicine but also paves the way for introducing decision theory into OMICS data science.

Pembrolizumab Induces an Unexpected Conformational Change in the CC'-loop of PD-1.

To improve cancer immunotherapy, a clearer understanding of key targets such as the immune checkpoint receptor PD-1 is essential. The PD-1 inhibitors nivolumab and pembrolizumab were recently approved by the FDA. The CC'-loop of PD-1 has been identified as a hotspot for drug targeting. Here, we investigate the influence of nivolumab and pembrolizumab on the molecular motion of the CC'-loop of PD-1. We performed molecular dynamics simulations on the complete extracellular domain of PD-1, in complex with PD-L1, and the blocking antibodies nivolumab and pembrolizumab. Conformations of the CC'-loop were analyzed unsupervised with the Daura et al. clustering algorithm and multidimensional scaling. Surprisingly, two conformations found were seen to correspond to the 'open' and 'closed' conformation of CC'-loop in apo-PD-1, already known from literature. Unsupervised clustering also surprisingly reproduced the natural ligand, PD-L1, exclusively stabilizing the 'closed' conformation, as also known from literature. Nivolumab, like PD-L1, was found to shift the equilibrium towards the 'closed' conformation, in accordance with the conformational selection model. Pembrolizumab, on the other hand, induced a third conformation of the CC'-loop which has not been described to date: Relative to the conformation 'open' the, CC'-loop turned 180° to form a new conformation which we called 'overturned'. We show that the combination of clustering and multidimensional scaling is a fast, easy, and powerful method in analyzing structural changes in proteins. Possible refined antibodies or new small molecular compounds could utilize the flexibility of the CC'-loop to improve immunotherapy.

The value of pretreatment serum butyrylcholinesterase level as a novel prognostic biomarker in patients with cervical cancer treated with primary (chemo-)radiation therapy.

BACKGROUND: Deficiency in butyrylcholinesterase (BChE), a condition commonly noticed in liver damage, inflammation, and malnutrition, has previously been associated with impaired prognosis in different malignancies. The aim of the present study was to investigate the value of pretreatment serum BChE levels as a prognostic biomarker in patients with cervical cancer treated with primary (chemotherapy-[chemo-])radiation therapy. METHODS: We retrospectively evaluated data of a consecutive series of patients with cervical cancer treated with primary (chemo-)radiation therapy between 1998 and 2015. Pretreatment serum BChE levels were correlated with clinico-pathological parameters and response to treatment. Uni- and multivariate survival analyses were performed to assess the association between decreased serum BChE levels and progression-free (PFS), cancer-specific (CSS), and overall survival (OS). RESULTS: A total of 356 patients were eligible for inclusion into the present study. The median (IQR) pretreatment serum BChE level was 6180 (4990-7710) IU/l. Lower serum BChE levels were associated with lower BMI (p < 0.001), advanced tumor stage (p = 0.04), poor treatment response (p = 0.002), the occurrence of disease recurrence (p = 0.003), and the risk of death (p < 0.001). In uni- and multivariate analyses, low pretreatment serum BChE levels were independently associated with shorter PFS (HR 1.8 [1.2-2.6]; p = 0.002), CSS (HR 2.2 [1.4-3.5], p < 0.001), and OS (HR 2.0 [1.4-2.9]; p < 0.001). CONCLUSIONS: Low pretreatment serum BChE levels are associated with advanced tumor stage and poor response to treatment, and serve as an independent prognostic biomarker for shorter PFS, CSS, and OS in patients with cervical cancer treated with primary (chemo-)radiation therapy.

Prolapse surgery versus vaginal pessary in women with symptomatic pelvic organ prolapse: which factors influence the choice of treatment?

OBJECTIVE: To investigate which specific clinical factors influence patients' choice of prolapse treatment. METHODS: This study includes a total of 510 cases with symptomatic pelvic organ prolapse (POP) of stage II or higher requiring prolapse treatment. Patients were divided into surgery and pessary groups according to their own choice and treatment preference. Primary outcome of interest was to define potential clinical parameters, which contribute to surgical treatment decision. RESULTS: A total of 252/510 (49%) women decided for prolapse surgery and 258/510 (51%) cases were treated conservatively with vaginal pessary. Hypertension, COPD as well as polypharmacy were parameters, which were statistically significantly more common in the pessary group compared to the surgically managed cases (p <0.05). On the contrary, women undergoing prolapse surgery were significantly younger and showed more advanced POP-Q (pelvic organ prolapse quantification) stages (p < 0.05). Clinical factors, such as BMI (body mass index), parity, mode of delivery and postmenopausal status, did not differ between the two groups (p > 0.05). Multiple logistic regression analysis revealed that advanced POP-Q stage (p < 0.001) as well as the absence of smoking (p < 0.001) were independent factors associated with surgical treatment decision. CONCLUSION: Women, who favoured prolapse surgery, were younger and in significant better health condition (less hypertension and COPD), but showed a significantly higher POP-Q stage compared to women choosing pessary treatment. Our data indicate that women with higher POP-Q stage and non-smokers tended to decide for prolapse surgery. This information could help in clinical practice to guide patients for the best possible treatment decision and strengthen individual counselling.

Association of uterine leiomyoma and overactive bladder syndrome.

OBJECTIVE: To assess associations between anterior and/or fundal uterine leiomyoma and overactive bladder syndrome. METHODS: The present cohort study recruited women diagnosed with fundal/anterior uterine leiomyoma by standardized transvaginal ultrasonography at the Medical University of Vienna, Austria, between January 1, 2010, and December 31, 2013, in addition to an age-matched control group of women without uterine leiomyoma. The International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OAB) was mailed to all eligible participants. The main outcome was the ICIQ-OAB sum score. RESULTS: Among 304 questionnaires sent out, 129 were returned. After the exclusion of incomplete datasets, 80 women were included in the analysis (uterine leiomyoma group, 43; control group, 37). The mean ± SD ICIQ-OAB sum score was 9.7 ± 10.2 for women with uterine leiomyoma and 4.2 ± 5.3 for women in the control group; thus, the ICIQ-OAB sum score was on average 5.5 points higher in the uterine leiomyoma group (P=0.003). The Spearman correlation coefficient between the total volume of leiomyoma per woman and the ICIQ-OAB sum score was 0.072 (P=0.645). CONCLUSION: The study found a significant association between anterior and/or fundal leiomyoma and overactive bladder syndrome. The presence of uterine leiomyoma should be ruled out during the evaluation of overactive bladder.

AB0 blood groups and rhesus factor expression as prognostic parameters in patients with epithelial ovarian cancer - a retrospective multi-centre study.

BACKGROUND: AB0 blood groups and Rhesus factor expression have been associated with carcinogenesis, response to treatment and tumor progression in several malignancies. The aim of the present study was to test the hypothesis that AB0 blood groups and Rhesus factor expression are associated with clinical outcome in patients with epithelial ovarian cancer (EOC). METHODS: AB0 blood groups and Rhesus factor expression were evaluated in a retrospective multicenter study including 518 patients with EOC. Their association with patients' survival was assessed using univariate and multivariable analyses. RESULTS: Neither AB0 blood groups nor Rhesus factor expression were associated with clinico-pathological parameters, recurrence-free, cancer-specific, or overall survival. In a subgroup of patients with high-grade serous adenocarcinoma, however, blood groups B and AB were associated with a better 5-year cancer-specific survival rate compared to blood groups A and 0 (60.3 ± 8.6% vs. 43.8 ± 3.6%, p = 0.04). Yet, this was not significant in multivariable analysis. CONCLUSIONS: AB0 blood groups and Rhesus factor expression are both neither associated with features of biologically aggressive disease nor clinical outcome in patients with EOC. Further investigation of the role of the blood group B antigen on cancer-specific survival in the subgroup of high-grade serous should be considered.

Association of endogenous circulating sex steroids and condition-specific quality of life domains in postmenopausal women with pelvic floor disorders.

OBJECTIVE: To examine the relationship between endogenous sex steroids and various condition-specific quality of life domains in postmenopausal women with pelvic floor disorders. We hypothesized that woman with lowest androgen and estradiol concentrations would report worse scores of quality of life domains. METHODS: Forty-six women with pelvic organ prolapse (POP) and 47 cases with stress urinary incontinence (SUI) answered the validated pelvic floor questionnaire and underwent serum sex steroid measurement. A multivariate logistic regression model was used to determine the association between subjective outcome parameters and serum hormonal levels after adjusting for confounders. RESULTS: Univariate analysis revealed a strong inverse correlation between serum estradiol level (E2) and prolapse domain score (correlation coefficient = 0.005) as well as a significant positive correlation between SHBG level and prolapse domain score (correlation coefficient = 0.019) in cases with POP. Furthermore, the sex domain score showed a significant negative correlation with the androstendion (correlation coefficient = 0.020), DHEAS (correlation coefficient = 0.046) and testosterone level (correlation coefficient = 0.032) in the POP group. In the multivariate model, high serum SHBG (CI: 0.007-0.046) remained independently associated with worse scores in the prolapse domain and low serum DHEAS (CI: - 0.989 to 1.320) persisted as a significant predictor for a worse score in the sex domain. Regarding SUI cases, no association was noted between serum hormonal levels and quality of life related pelvic floor domains (correlation coefficient > 0.05). CONCLUSION: Our results suggest that pelvic floor related quality of life might also be affected by endogenous sex steroids in POP, but not in SUI cases.

Gene expression information improves reliability of receptor status in breast cancer patients.

Immunohistochemical (IHC) determination of receptor status in breast cancer patients is frequently inaccurate. Since it directs the choice of systemic therapy, it is essential to increase its reliability. We increase the validity of IHC receptor expression by additionally considering gene expression (GE) measurements. Crisp therapeutic decisions are based on IHC estimates, even if they are borderline reliable. We further improve decision quality by a responsibility function, defining a critical domain for gene expression. Refined normalization is devised to file any newly diagnosed patient into existing data bases. Our approach renders receptor estimates more reliable by identifying patients with questionable receptor status. The approach is also more efficient since the rate of conclusive samples is increased. We have curated and evaluated gene expression data, together with clinical information, from 2880 breast cancer patients. Combining IHC with gene expression information yields a method more reliable and also more efficient as compared to common practice up to now. Several types of possibly suboptimal treatment allocations, based on IHC receptor status alone, are enumerated. A 'therapy allocation check' identifies patients possibly miss-classified. Estrogen: false negative 8%, false positive 6%. Progesterone: false negative 14%, false positive 11%. HER2: false negative 2%, false positive 50%. Possible implications are discussed. We propose an 'expression look-up-plot', allowing for a significant potential to improve the quality of precision medicine. Methods are developed and exemplified here for breast cancer patients, but they may readily be transferred to diagnostic data relevant for therapeutic decisions in other fields of oncology.

Role of serum steroid hormones in women with stress urinary incontinence: a case-control study.

OBJECTIVES: To investigate the potential relationship between endogenous sex steroids and presence of stress urinary incontinence (SUI). PATIENTS AND METHODS: A total of 47 peri- and postmenopausal women with SUI were matched 1:1 with 47 continent women based on age, menopausal status, body mass index (BMI) and parity. Blood samples were drawn from all the women for assessment of oestradiol (E2), follicle-stimulating hormone, luteinizing hormone, testosterone, androstendion (AEON), dehydroepiandrosterone sulphate and sex hormone-binding globulin with an electrochemiluminescence immunoassay. RESULTS: Women with SUI had significantly lower serum levels of E2 (8.49 ± 7.47 vs 13.09 ± 13.80; P = 0.048) and AEON (0.59 ± 0.41 vs 1.20 ± 0.87; P = 0.033) compared with controls. This difference in E2 levels remained significant after controlling for age, menopausal age, years from menopause, BMI, parity, testosterone and AEON. In addition, hypertension and history of hysterectomy were observed significantly more frequently in the SUI group (P < 0.001). There was no significant association between hormone levels and degree of SUI (P > 0.05). CONCLUSION: The results of the present study indicate that a low E2 level might have a negative impact on the lower urinary tract and continence mechanism and a low E2 level is a possible risk factor for SUI in women.

Consensus Statement of the European Urology Association and the European Urogynaecological Association on the Use of Implanted Materials for Treating Pelvic Organ Prolapse and Stress Urinary Incontinence.

CONTEXT: Surgical nonautologous meshes have been used for several decades to repair abdominal wall herniae. Implantable materials have been adopted for the treatment of female and male stress urinary incontinence (SUI) and female pelvic organ prolapse (POP). OBJECTIVE: A consensus review of existing data based on published meta-analyses and reviews. EVIDENCE ACQUISITION: This document summarises the deliberations of a consensus group meeting convened by the European Association of Urology (EAU) and the European Urogynecological Association, to explore the current evidence relating to the use of polypropylene (PP) materials used for the treatment of SUI and POP, with reference to the 2016 EAU guidelines (European Association of Urology 2016), the European Commission's SCENIHR report on the use of surgical meshes (SCENIHR 2015), other available high-quality evidence, guidelines, and national recommendations. EVIDENCE SYNTHESIS: Current data suggest that the use of nonautologous durable materials in surgery has well-established benefits but significant risks, which are specific to the condition and location they are used for. Various graft-related complications have been described-such as infection, chronic pain including dyspareunia, exposure in the vagina, shrinkage, erosion into other organs of xenografts, synthetic PP tapes (used in SUI), and meshes (used in POP)-which differ from the complications seen with abdominal herniae. CONCLUSIONS: When considering surgery for SUI, it is essential to evaluate the available options, which may include synthetic midurethral slings (MUSs) using PP tapes, bulking agents, colposuspension, and autologous sling surgery. The use of synthetic MUSs for surgical treatment of SUI in both male and female patients has good efficacy and acceptable morbidity. Synthetic mesh for POP should be used only in complex cases with recurrent prolapse in the same compartment and restricted to those surgeons with appropriate training who are working in multidisciplinary referral centres. PATIENT SUMMARY: Synthetic slings can be safely used in the surgical treatment of stress incontinence in both male and female patients. Patients need to be aware of the alternative therapy and potential risks and complications of this therapy. Synthetic mesh for treating prolapse should be used only in complex cases with recurrent prolapse in specialist referral centres.

Management of vesicovaginal fistulas (VVFs) in women following benign gynaecologic surgery: A systematic review and meta-analysis.

BACKGROUND: Vesicovaginal fistulas (VVF) are the most commonly acquired fistulas of the urinary tract, but we lack a standardized algorithm for their management. Surgery is the most commonly preferred approach to treat women with primary VVF following benign gynaecologic surgery. OBJECTIVE: To carry out a systematic review and meta-analysis on the effectiveness of operative techniques or conservative treatment for patients with postsurgical VVF. Our secondary objective was to define the surgical time and determine the types of study designs. METHODS: PubMed, Old Medline, Embase and Cochrane Central Register of Controlled Trials were used as data sources. This systematic review was modelled on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, including a registration number (CRD42012002097). RESULTS: We reviewed 282 full text articles to identify 124 studies for inclusion. In all, 1379/1430 (96.4%) patients were treated surgically. Overall, the transvaginal approach was performed in the majority of patients (39%), followed by a transabdominal/transvesical route (36%), a laparoscopic/robotic approach (15%) and a combined transabdominal-transvaginal approach in 3% of cases. Success rate of conservative treatment was 92.86% (95%CI: 79.54-99.89), 97.98% in surgical cases (95% CI: 96.13-99.29) and 91.63% (95% CI: 87.68-97.03) in patients with prolonged catheter drainage followed by surgery. 79/124 studies (63.7%) provided information for the length of follow-up, but showed a poor reporting standard regarding prognosis. Complications were studied only selectively. Due to the inconsistency of these data it was impossible to analyse them collectively. CONCLUSIONS: Although the literature is imprecise and inconsistent, existing studies indicate that operation, mainly through a transvaginal approach, is the most commonly preferred treatment strategy in females with postsurgical VVF. Our data showed no clear odds-on favorite regarding disease management as well as surgical approach and current evidence on the surgical management of VVF does not allow any accurate estimation of success and complication rates. Standardisation of the terminology is required so that VVF can be managed with a proper surgical treatment algorithm based on characteristics of the fistula.

The Impact of the Duration of Adjuvant Chemotherapy on Survival in Patients with Epithelial Ovarian Cancer - A Retrospective Study.

OBJECTIVE: The aim of the present study was to investigate the prognostic role of the duration of adjuvant chemotherapy in patients with epithelial ovarian, fallopian tube and primary peritoneal cancer (EOC). MATERIALS AND METHODS: Within the present study we retrospectively evaluated the data of 165 consecutive patients with EOC treated with primary surgery followed by six completed cycles of platinum-taxan based intravenous adjuvant chemotherapy. Medians of total duration of chemotherapy were compared with clinical-pathological parameters. Patients were stratified into four risk groups according to the delay in days of total duration of chemotherapy, and univariate and multivariable survival analyses were performed. RESULTS: The median duration of six completed cycles of chemotherapy comprised 113 days (IQR 107-124 days). Uni- and multivariable survival analyses revealed a delay of total duration of chemotherapy of at least 9 days to be associated with progression-free (PFS), cancer-specific (CSS) and overall survival (OS). Hazard ratios (HR), confidence intervals (95% CI) and p-values for PFS, CSS and OS due to delay of chemo-duration were 2.9 (1.6-5.4; p = 0.001), 2.9 (1.3-6.2; p = 0.008) and 2.6 (1.3-5.4; p = 0.008), respectively. Prolonged total chemo-duration was associated with the amount of postoperative residual disease (p = 0.001) and the patients' age (p = 0.03). CONCLUSION: The present study suggests a prolonged duration of adjuvant chemotherapy after primary surgery to adversely affect PFS, CSS and OS in patients with EOC. Yet larger studies are required to validate our results.

The role of fibroblast growth factor 2 in patients with uterine smooth muscle tumors: an immunohistochemical study.

OBJECTIVE: Fibroblast growth factor 2 (FGF-2) is considered to be a potent stimulator of angiogenesis and seems therefore to play an important role in the growth of tumors. We compared the immunohistochemical profile of FGF-2 in patients with uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we tried to clarify the prognostic role of FGF-2 in uterine leiomyosarcoma. STUDY DESIGN: FGF-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 cases with STUMP and in 21 patients with LMS. The immunohistochemical profile of these 3 tumor entities was compared and regarding LMS correlated with different clinicopathologic parameters. RESULTS: FGF-2 was expressed in 85% of leiomyomas, in 88% of STUMP and in 57% of LMS. Significant differences regarding the frequency of FGF-2 expression were observed between leiomyoma and LMS as well as between STUMP and LMS (p<0.05). In uterine LMS FGF-2 expression was statistically more frequent in cases with high histological grade (p<0.05). Furthermore, FGF-2 positive tumors demonstrated a statistically significant higher rate of recurrence disease and tumor progression (p=0.005). Disease free as well as overall survival was significantly shortened in patients with FGF-2 positive compared to FGF-2 negative tumors (p<0.05). CONCLUSION: The significant correlation between FGF-2 expression and high histological grade indicates that FGF-2 might work as a negative predictive factor. Higher rates of recurrence disease as well as shortened disease free and overall survival among FGF-2 positive LMS support the potential role as prognosticator for poor clinical outcome.

The prognostic role of metformin in patients with endometrial cancer: a retrospective study.

OBJECTIVE: Metformin has recently been discussed to possess anticancer activities and to positively affect the risk of developing cancer. We performed the present study to investigate the association of metformin and survival in patients with endometrial cancer. STUDY DESIGN: Within the present study we retrospectively reviewed the records of 465 consecutive patients with endometrial cancer. Drug intake of metformin was correlated with clinico-pathological parameters and the patients' survival. Chi-square test, Kruskal Wallis test, the product limit method of Kaplan and Meier, and multivariable Cox regression models were used to assess associations between metformin and clinico-pathological parameters and survival, as appropriate. RESULTS: Eighty-seven (18.7%) patients suffered from diabetes and of these 46 (52.8%) used metformin at the time of diagnosis. When analysing all patients, metformin did not affect the patients' survival. However, within the subgroup of overweight patients metformin was associated with a prolongation of overall survival (p=0.04). Within this subgroup, diabetic patients who did not use metformin had a 2.3 times higher risk for death (95%CI 1.1-4.7; p=0.02) compared to non-diabetic patients and diabetic patients using metformin. Metformin was not associated with prolonged recurrence-free or cancer-specific survival, irrespective of the patients' body mass index (p=0.08 and p=0.4, respectively). CONCLUSION: The results of our study might suggest a beneficial effect of metformin on overall survival in overweight diabetic patients with endometrial cancer. However, the question, if metformin can reduce the risk to die from endometrial cancer or improves all cause mortality only still remains open and needs further investigation.