Markus Wallwiener

Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay.

It has been hypothesized that carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, although the presence of CTCs is an indicator of poor prognosis in several carcinoma entities, the existence and phenotype of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. Here we developed a xenograft assay and used it to show that primary human luminal breast cancer CTCs contain MICs that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. In a small cohort of patients with metastases, the number of EPCAM+CD44+CD47+MET+ CTCs, but not of bulk EPCAM+ CTCs, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer.

Circulating miRNAs as Surrogate Markers for Circulating Tumor Cells and Prognostic Markers in Metastatic Breast Cancer

Purpose: The use of circulating tumor cells (CTC) as a prognostic marker in metastatic breast cancer (MBC) has been well established. However, their efficacy and accuracy are still under scrutiny mainly because of methods of their enrichment and identification. We hypothesized that circulating miRNAs can predict the CTC status of patients with MBC, and tested for the same. Furthermore, we aimed at establishing a panel of circulating miRNAs capable of differentiating MBC cases from healthy controls. Experimental Design: Circulating miRNAs from plasma of CTC-positive and CTC-negative patients with MBC, and healthy controls, were profiled by TaqMan Human MicroRNA arrays. Candidates from the initial screen were validated in an extended cohort of 269 individuals (61 CTC-positive, 72 CTC-negative, 60 CTC-low MBC cases, and 76 controls). Results: CTC-positive had significantly higher levels of miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-375, and miR-801 than CTC-negative MBC and controls (P < 0.00001), whereas miR-768-3p was present in lower amounts in MBC cases (P < 0.05). miR-200b was singled out as the best marker for distinguishing CTC-positive from CTC-negative patients (AUC 0.88). We identified combinations of miRNAs for differentiating MBC cases from controls (AUC 0.95 for CTC-positive; AUC 0.78 for CTC-negative). Combinations of miRNAs and miR-200b alone were found to be promising prognostic marker for progression-free and overall survival. Conclusion: This is the first study to document the capacity of circulating miRNAs to indicate CTC status and their potential as prognostic markers in patients with MBC. Clin Cancer Res; 18(21); 5972–82. ©2012 AACR.

Prevalence of Sexual Dysfunction and Impact of Contraception in Female German Medical Students

INTRODUCTION Female sexual dysfunction (FSD) is a very common disorder, with an estimated prevalence of having at least one sexual dysfunction of about 40%. AIM To investigate the prevalence and types of FSD and the relationship between hormonal contraception (HC) and FSD in female German medical students. MAIN OUTCOME MEASURES Female Sexual Function Index (FSFI) with additional questions on contraception, sexual activity, and other factors that may influence sexual function. METHODS An online questionnaire based on the FSFI was completed by students from six medical schools. Obtained data were screened for inconsistencies by programmed algorithms. RESULTS A total of 1,219 completed questionnaires were received, and 1,086 were included in the analyses after screening. The mean total FSFI score was 28.6 +/- 4.5. 32.4% of women were at risk for FSD according to FSFI definitions. Based on domain scores, 8.7% for were at risk for FSD concerning orgasm, 5.8% for desire, 2.6% for satisfaction, 1.2% for lubrication, 1.1% for pain and 1.0% for arousal. The method of contraception and smoking were factors with significant effect on the total FSFI score whereby hormonal contraception was associated with lower total FSFI scores and lower desire and arousal scores than no contraception and non-hormonal contraception only. Other variables such as stress, pregnancy, smoking, relationship and wish for children had an important impact on sexual function as expected according to earlier studies. CONCLUSIONS The prevalence of students at high risk for FSD was consistent with the literature although domain subscores differed from samples previously described. The contraception method has a significant effect on the sexual functioning score and women using contraception, especially hormonal contraception, had lower sexual functioning scores. Stress and relationship among other variables were found to be associated with sexual function and may thus provide insight into the etiology of sexual disorders.

Intra-abdominal adhesions: definition, origin, significance in surgical practice, and treatment options.

BACKGROUND Intra-abdominal adhesions arise after more than 50% of all abdominal operations and are an important source of postoperative complications. They attach normally separated organs to each other and can cause major problems for the affected patients by giving rise to small bowel obstruction, chronic pelvic pain, dyspareunia, infertility, and higher complication rates in subsequent operations. They are also a frequent source of medicolegal conflict. Thus, every physician should be familiar with their mechanism of origin, their consequences, and the methods by which they can be prevented. METHODS A selective PubMed/Medline search from 1960 onward as well as articles to which these publications referred. The expert consensus position of the European Society for Gynaecological Surgery is also taken into consideration. RESULTS Adhesions arise through aberrant wound healing after peritoneal injury with further influence from a variety of other factors. Preventive measures include minimizing peritoneal injury intraoperatively through the meticulous observance of basic surgical principles, moistening the mesothelium to keep it from drying out, irrigating the peritoneal cavity to remove blood and clot, and keeping the use of intra-abdominal foreign material to a minimum. CONCLUSION Adhesions are an inevitable consequence of intra-abdominal surgery. They can be prevented to some extent with meticulous surgical technique and certain other measures. For operations carrying a high risk of postoperative adhesions, e.g., surgery on the adnexa or bowel, commercially available peritoneal instillates or barrier methods can be used to limit adhesion formation.

Impact of electronic messaging on the patient-physician interaction:

Patients are interested in secure electronic communication with their health-care providers, but physicians have been slow to adopt the technique into their practice. We have therefore reviewed the literature on secure patient messaging. Relevant studies were identified by Medline search which produced 1065 publications. Of these, 71 relevant articles were read independently by two reviewers. Currently available messaging systems allow for asynchronous communication, physician reimbursement and automated supporting functions such as triaging of patient messages and integration of messaging into medical records. The review showed that patients are satisfied with the use of secure physician messaging systems and find such services to be convenient, time-saving and useful. Physicians do not report adverse effects from their use. Legal concerns with electronic messaging include compliance with privacy standards. The economic benefits of secure messaging systems are most immediately apparent for larger health-care groups and hospitals, although smaller practices will also benefit in the long run. Secure patient-physician messaging is a convenient and useful addition to the health-care infrastructure. It can be expected that the identification of secure providers, integration with reimbursement systems and initial uptake by larger health-care organizations will speed up the adoption into routine health care.

A direct comparison of seprafilm, adept, intercoat, and spraygel for adhesion prophylaxis.

BACKGROUND Commercially available agents for adhesion prophylaxis are legion but there is a lack of direct comparisons between them. Here we compare four of the most commonly used adhesion barriers against a control group in a clinically relevant rat model. MATERIAL AND METHODS Standardized lesions were created in Wistar rats using electrocautery and suturing. Subsequently, the experimental lesions were treated with Seprafilm (n = 30), Adept (n = 30), Intercoat (n = 30), Spraygel (n = 30), or no barrier (n = 30). The resulting adhesions were examined 14 d postoperatively. RESULTS The mean area covered by adhesion was 77% in the control group, 46% in animals treated with Seprafilm, 54% in animals treated with Adept, 55% in animals treated with Intercoat, and 68% in animals treated with Spraygel. The adhesion-free incidence was 20% (n = 6) of lesions treated with Seprafilm, 20% (n = 6) of lesions treated with Intercoat, 3% of lesions treated with Spraygel (n = 1), and 0% of lesions treated with Adept or the control group. CONCLUSIONS There were statistically significant differences between the barriers with regards to the area covered by adhesions and the adhesion-free incidence. In spite of this, a significant adhesion burden remains with all of the tested barriers.

Intraperitoneal adhesions—An ongoing challenge between biomedical engineering and the life sciences

Peritoneal adhesions remain a relevant clinical problem despite the currently available prophylactic barrier materials. So far, the physical separation of traumatized serosa areas using barriers represents the most important clinical strategy for adhesion prevention. However, the optimal material has not yet been found. Further optimization or pharmacological functionalization of these barriers could give an innovative input for peritoneal adhesion prevention. Therefore, a more complete understanding of pathogenesis is required. On the basis of the pathophysiology of adhesion formation the main barriers currently in clinical practice as well as new innovations are discussed in the present review. Physiologically, mesothelial cells play a decisive role in providing a frictionless gliding surface on the serosa. Adhesion formation results from a cascade of events and is regulated by a variety of cellular and humoral factors. The main clinically applied strategy for adhesion prevention is based on the use of liquid or solid adhesion barriers to separate physically any denuded tissue. Both animal and human trials have not yet been able to identify the optimal barrier to prevent adhesion formation in a sustainable way. Therefore, further developments are required for effective prevention of postoperative adhesion formation. To reach this goal the combination of structural modification and pharmacological functionalization of barrier materials should be addressed. Achieving this aim requires the interaction between basic research, materials science and clinical expertise.

Circulating miRNAs with prognostic value in metastatic breast cancer and for early detection of metastasis

Metastasis is the principal cause of high morbidity and mortality among breast cancer (BC) patients. Identification of markers that can be routinely monitored to predict onset of metastasis in BC patients and prognosis of metastatic breast cancer (MBC) patients would increase their median survival. In this study, plasma miRNAs of 40 MBC patients were profiled by TaqMan low density arrays and miRNAs with prognostic capacity were identified. The candidates were validated initially in the samples of 237 MBC patients and subsequently in 335 samples from an independent study cohort of BC patients. Sixteen miRNAs were established to be significantly associated with overall survival, and were termed as prognostic miRNA panel template (PROMPT). These included miR-141, miR-144, miR-193b, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-215, miR-365, miR-375, miR-429, miR-486-5p, miR-801, miR-1260 and miR-1274a. Additionally, 11 of these miRNAs were also associated with progression-free survival. Their prognostic significance was further confirmed in samples from a second study cohort of BC patients. In addition, miR-200a, miR-200b, miR-200c, miR-210, miR-215 and miR-486-5p were found to be significantly associated with onset of metastasis up to 2 years prior to clinical diagnosis in BC patients. We have thus identified panels of miRNAs, which include metastasis promoting miR-200 family and miR-203, as well as oncogenic and tumor-suppressive miRNAs, that can serve as prognostic markers for MBC, and early detection markers of metastasis in BC.

Thermal Conduction, Compression, and Electrical Current–An Evaluation of Major Parameters of Electrosurgical Vessel Sealing in a Porcine In Vitro Model

Bipolar vessel sealing is pivotal in laparoscopic hemostasis. However, major coaptive desiccation parameters have yet to be investigated in detail. The current investigation aims to study the impact of compressive pressure, thermal conduction, and electrical current effects on seal quality in a randomized, controlled experimental trial in an in vitro porcine model of vessel sealing. A total of 106 porcine vessels were sealed with either bipolar current or thermal conduction. Compressive pressure on the sealing site and maximum temperature were varied and monitored. Additionally, the longitudinal vessel tension was measured. The burst pressure of the resulting seal was determined as an indicator of seal quality. In bipolar coaptation, seal quality depends on the compressive pressure applied to the coagulation site in both arteries and veins. The optimal pressure interval was around 270 mN/mm2 for arteries and 200 mN/mm2 for veins. Deviation from these optimal pressures towards low and high extremes led to significantly fewer successful seals. We also found that both maximum coaptation temperature and vessel shrinking correlated with the seal quality. This correlation was reciprocal in arteries and veins. Thermal conduction alone was less successful than sealing by bipolar current. Therefore, compressive pressure during coaptation determines the seal quality. Upper and lower pressure boundaries for safe coaptation exist for both arteries and veins. Vessel sealing by thermal conduction without electrical current effects is possible but represents a less effective method for coaptation. These findings have implications for the rational design of new electrosurgical instruments.

Effects of sex hormones in oral contraceptives on the female sexual function score: a study in German female medical students

BACKGROUND The survey was conducted to compare the influence of sex hormones in oral contraceptives (OCs) on female sexual function. METHODS One thousand eighty-six female German medical students completed an online-based questionnaire incorporating the Female Sexual Function Index (FSFI). Oral contraceptives used were classified into those containing androgenic or antiandrogenic progestins and by ethinylestradiol (EE) dosage (20 mcg, 30 mcg and >30 mcg). Female Sexual Function Index scores in women using OCs were compared to those in nonusers. RESULTS Seven hundred fifty-two of 1086 participating women used OCs. No statistically significant differences in FSFI scores were found among women using OCs containing androgenic or antiandrogenic progestins, nor were any seen between different EE dosages. In general, OC users had lower FSFI scores than nonusers. CONCLUSION Female Sexual Function Index scores were negatively influenced by the use of OCs. However, the impact of an androgenic or antiandrogenic progestin content or different dosages of EE as modulating factors of female sexual function seems negligible.