Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

Unilateral pectineal suspension - A new surgical approach for apical correction of pelvic organ prolapse.

Background and objectives: There are numerous vaginal and abdominal surgical approaches for the treatment of pelvic organ prolapse (POP). Even the standard techniques show great variability due to modifications depending on anatomy, available instruments and materials. Recently, the role of hysterectomy in prolapse surgery as well as the use of synthetic meshes have been questioned. Here, we present a standardised mesh-free minimally invasive pelvic floor reconstruction technique with uterus preservation. Materials and Methods: Unilateral pectineal suspension (UPS) is carried out in five defined steps with the use of the da Vinci Xi ® surgical system. The desired anatomical result is simulated by intraoperative uterus manipulation. The cranial part of the pectineal ligament is used for lateral fixation. A non-absorbable suture is placed between the pectineal ligament and the anterior cervix to suspend the uterus in its natural anatomical position. Main outcome measures: For outcome measurement, degree of prolapse was assessed pre- and postoperatively according to the POP-Q system. Results: Unilateral pectineal suspension offers several advantages. Medial tension-free positioning of the uterus is achieved. The use of the cervix as fixation structure allows for excellent pelvic floor support and stable results. Normal pelvic floor mobility and natural axis of the vagina are restored. Conclusions: Unilateral pectineal suspension is an efficient minimal-invasive mesh-free procedure which allows uterus preservation and offers reliable level I support respecting the physiological pelvic anatomy. In addition, there is no need for ureteral dissection or bowel manipulation. The technique offers clinical standardization and can easily be integrated into the spectrum of modern surgical POP repair.

Complementary and alternative medicine and musculoskeletal pain in the first year of adjuvant aromatase inhibitor treatment in early breast cancer patients.

BACKGROUND: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment. PATIENTS AND METHODS: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points. RESULTS: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use. CONCLUSIONS: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study.

BACKGROUND: Endocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor-positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. PATIENTS AND METHODS: Post-menopausal hormone receptor-positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. RESULTS: Among 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90-3.42), sleep disorders (HR 1.95; 95% CI, 1.41-2.70) and other AEs (HR 2.03; 95% CI, 1.51-2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74-1.84). CONCLUSIONS: These results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. CLINICAL TRIALS NUMBER: CFEM345DDE19.

A Review of Integrative Medicine in Gynaecological Oncology.

In recent years complementary and alternative medicine (CAM) has increasingly been the focus of international research. Numerous subsidised trials (7903) and systematic reviews (651) have been published, and the evidence is starting to be integrated into treatment guidelines. However, due to insufficient evidence and/or insufficient good quality evidence, this has mostly not translated to practice recommendations in reviews by the Cochrane collaboration gynaecology group. There is nevertheless a not insignificant number of CAM providers and users. The percentage of oncology patients who use CAM varies between 5 and 90 %. Doctors have been identified as the main providers of CAM. Half of gynaecologists offer CAM because of personal conviction or on suggestion from colleagues. This must be viewed in a critical light, since CAM is mostly practiced without appropriate training, often without sufficient evidence for a given method - and where evidence exists, practice guidelines are lacking - and lack of safety or efficacy testing. The combination of patient demand and lucrativeness for doctors/alternative medicine practitioners, both based on supposed effectiveness CAM, often leads to its indiscriminate use with uncertain outcomes and significant cost for patients. On the other hand there is published, positive level I evidence for a number of CAM treatment forms. The aim of this article is therefore to review the available evidence for CAM in gynaecological oncology practice. The continued need for research is highlighted, as is the need to integrate practices supported by good evidence into conventional gynaecological oncology.

Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro.

The catecholamines norepinephrine and dopamine (DA) are present in the human ovary; in particular, in follicular fluid. Norepinephrine activates ovarian alpha- and beta-adrenergic receptors and modulates ovarian steroidogenesis, but the significance of ovarian DA is unclear. We examined whether a DA receptor of the D1-subtype (D1-R) is present in human ovary and in cultured human granulosa luteal cells (GC). Using RT-PCR, we cloned complementary DNAs from adult human ovarian and GC messenger RNAs, which are identical to the human D1-R sequence. In ovarian sections, D1-R protein was identified (by immunohistochemistry) in granulosa cells of large antral follicles, cells of the corpus luteum, as well as in cultured GC. An immunoreactive band of approximately Mr 50,000 was found in cultured luteinized GC using the same antiserum in Western blots. The D1-R in these cells was functional, because DA, alone or in the presence of the beta-receptor antagonist propranolol, caused cellular contraction. The selective D1-R agonist SKF-38393 induced a similar change in cytomorphology and increased the levels of media cAMP. SKF-38393 failed, however, to significantly affect basal and hCG-stimulated progesterone release in vitro, indicating that the activation of the D1-R was not directly linked to synthesis of progesterone, the major steroid of human GC. Estradiol synthesis likewise was not affected. Using RT-PCR and immunohistochemistry, we found that GC express DA- and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32), a protein typically associated with neurons bearing the D1-R. In cultured GC, DA and SKF-38393 induced increased threonine-phosphorylation of DARPP-32, even in the presence of propranolol but not in the presence of D1-R antagonist SCH-23390. Taken together, the presence of DA and a functional DA receptor and DARPP-32 indicate that a novel, physiological regulatory pathway involving DA exists in the human ovary.

Functional and molecular characterization of a muscarinic receptor type and evidence for expression of choline-acetyltransferase and vesicular acetylcholine transporter in human granulosa-luteal cells.

Previously, we provided evidence for the presence of a class of muscarinic receptors on human luteinized granulosa cells (human GC) that is linked to transient increases in intracellular free calcium levels, but not to steroid production. The precise nature of the receptor is not known, and neither its function nor the source of its natural ligand acetylcholine (ACh) is clear. To address these issues we used RT-PCR approaches and isolated complementary DNAs corresponding to the M1 receptor subtype from reverse transcribed human GC messenger ribonucleic acids. M1 receptors were further shown by immunocytochemistry, using a M1 receptor antiserum. Single cell calcium measurements showed that the M1 receptor was functionally active and linked to acute increases in intracellular free calcium, as the M1 receptor specific antagonist pirenzepine blocked the Ca2+-mobilizing effect of oxotremorine M (a muscarinic agonist). An unexpected consequence of M1 receptor activation was evidenced by the ability of muscarinic agonists to stimulate the proliferation of human GC within 24 h. In vivo, ACh, the natural ligand of these receptors is thought to be contained in cholinergic nerve fibers innervating the ovary. Surprisingly, the prerequisite for the synthesis of ACh, the enzyme choline-acetyltransferase (ChAT), is also expressed by human GC, as shown by Western blotting and immunocytochemistry. In addition, these cells express another marker for ACh synthesis, namely the gene for the vesicular acetylcholine transporter, as evidenced by RT-PCR cloning, Western blotting, and immunocytochemistry. In conclusion, our data identify the M1 receptor in human GC and point to a novel, trophic role of the neurotransmitter ACh. Furthermore, the presence of the prerequisites of ACh synthesis in human GC indicate that an autocrine/paracrine regulatory loop also exists in the in vivo counterparts of these cells in the ovary, i.e. in the cells of the preovulatory follicle and/or of the young corpus luteum.

Use of OKT3 hybridoma cells to clonally activate CD3+ human T lymphocytes.

A simple and reliable method was developed to induce clonal growth of resting human T cells. In this limiting dilution (LD) culture system, responder cells (unseparated mononuclear cells, E rosette-purified T cells, or cell sorter-separated CD4+ and CD8+ subsets) were activated by irradiated anti-CD3-secreting (OKT3) hybridoma cells in the presence of exogenous IL-2 (crude culture supernatant or recombinant IL-2). Under these conditions, one out of 2-3 CD4+ and CD8+ T cells developed into a proliferating cell clone. Addition of recombinant IL-1 slightly enhanced the growth frequency and increased the clone size of CD4+ cells but did not affect the growth pattern of CD8+ cells.

Clonal activation of cytotoxic lymphocyte precursors by monoclonal anti-CD3 antibody: analysis of feeder cell requirements.

Activation of cytotoxic lymphocyte precursors (CLP) by the mitogenic monoclonal anti-CD3 antibody OKT3 was studied under limiting dilution (LD) culture conditions. One out of 2-6 E-rosette-purified T cells gave rise to a cytotoxic T cell (CTL) clone when cultured in the presence of OKT3 (0.2-2 ng/ml), recombinant IL-2 (100 U/ml), and irradiated feeder cells. Clonal CLP activation was optimally supported by a combination of E-rosette-depleted non-T feeder cells with small numbers of T cells added back. Among the cell lines tested, Fc-receptor-bearing monocytic cell lines U937 and HL-60 were efficient feeder cells whereas T cell lines (Jurkat, Molt-4, Ke37) did not support clonal CLP activation. These data indicate that clonal activation of CLP and differentiation into cytotoxic effector cells under LD culture conditions are critically influenced by the type and number of feeder cells used.

Effect of motile sperm count after swim-up on outcome of intrauterine insemination.

OBJECTIVE: To analyze the prognostic value of motile sperm count after swim-up in IUI with husband's sperm in a large group of subfertile couples. DESIGN: Retrospective study. SETTING: University hospital. PATIENT(S): Nine hundred two couples undergoing 3,037 treatment cycles. INTERVENTION(S): Intrauterine insemination with husband's sperm after swim-up was performed after mild ovarian stimulation with clomiphene citrate and hCG under hormonal and ultrasonographic control of follicle development. MAIN OUTCOME MEASURE(S): Pregnancy rate (PR) in correlation to motile sperm count after swim-up. RESULT(S): A nonlinear increase in PR per treatment cycle was observed with increasing numbers of motile sperm used for IUI. Insemination with < 0.8 x 10(6) motile sperm after swim-up resulted in a PR of < 1% per treatment cycle. When the motile sperm count was above this level, the PR per cycle reached a plateau of 6.9% to 10.2%, with a minor tendency for increase with higher sperm numbers. CONCLUSION(S): Strict analysis of motile sperm count after swim-up is a useful prognostic factor for PRs after IUI. There is a good chance for conception if > or = 0.8 x 10(6) motile sperm are available after appropriate selection methods. Intrauterine insemination performed with considerably higher numbers of motile sperm does not lead to a significant increase in PRs.

The surgical trauma of abdominal wall incision. A comparison of laparoscopic vs open surgery with three-dimensional stereography.

BACKGROUND: Laparoscopic operations seem to respect the integrity of the abdominal wall better than conventional laparotomy, but the effects of surgical trauma are not well understood. The new technique of three-dimensional stereography makes it possible to describe and calculate the mobility of the abdominal wall and the nature of the underlying disturbances. METHODS: Three-dimensional stereography is a noninvasive optical method of measuring surface areas. Abdominal wall mobility can be assessed by comparing changes to the abdominal surface in its minimum and maximum excursions. Different parameters, such as height difference and curvature, are calculated. We studied patients undergoing different types of surgical procedures (laparoscopy and open surgery) by measuring their abdominal wall mobility before and after the procedure. We also compared these patients to a control group. Each group consisted of 30 patients, who were evaluated prospectively. RESULTS: We found a significant difference in abdominal wall mobility between patients treated via a laparoscopic approach, and those who had conventional surgery. At 7 days after laparoscopy, abdominal movement was always the same in the laparoscopic group as in the controls. By contrast, the open surgery group still showed a significant lack of mobility 12 days after the procedure. CONCLUSION: The new method of three-dimensional stereography makes it possible to compare the trauma associated with different surgical approaches as it affects the integrity of the abdominal wall. As compared with open surgery, laparoscopy has a significant positive effect on abdominal wall integrity.

[Pathophysiology of the abdominal wall]. / Pathophysiologie der Bauchdecken.

The use of biomaterials for closure of incisional hernias requires meshes adjusted to the physiological forces. The intraabdominal pressure is mainly influenced by the activity of the transverse muscles. The abdominal fascia of corpses withstands forces of 60-80 N/cm in horizontal and 20-30 N/cm in vertical direction; tearing of sutures occurs below 30 N/cm in horizontal direction. Assuming the abdominal cavity to be a thin hollow sphere, the rupture forces are approximately 4-16 N/cm for a diameter of 8-3 cm. The meshes currently in use are much stronger than this, rupturing at 40-100 N/cm. The curvature of the abdominal surface can be measured by 3D-photogrammetry and is highly significantly reduced following mesh implantation (t-test, 2-sided, P < 0.01). Reduction of the mesh material can decrease the rate of local wound complications and the stiffness of the abdominal wall.

Axial flow catheter pump for circulatory support.

AIM: The development of a percutaneously insertable catheter pump for temporary left ventricular and circulatory support in patients with acute ischemic cardiomyopathy. MATERIAL AND METHODS: The expandable axial flow pump (introduction diameter 9-F, expanded diameter 6.5 mm) is mounted at the tip of a catheter, designed to be placed in aortic transvalvular position. Hydrodynamic tests were performed in a static flow model and in a pulsatile mock circuit (Medos VAD, Stolberg, Germany). Cardiogenic shock was simulating in vitro and in vivo. RESULTS: At a rotation speed of 32,000 rpm the catheter pump delivered a maximum flow of more than 4.0 L/min against a systemic mean pressure of 60 mmHg. Under shock simulation the pump significantly improved output and systemic pressure. CONCLUSION: A percutaneously insertable catheter pump is technically feasible. Hydrodynamic efficacy allows sufficient cardiac support under simulated shock condition.

[Vaginal bleeding and premature contractions during pregnancy in uterus bicornis with expulsion of a decidual polyp]. / Ausstossung eines Deziduapolypen aus dem nichtgraviden Uterushorn bei einer Schwangerschaft mit Uterus bicornis.

Diagnosis and clinical course of a rare case are described, and the importance of prenatal ultrasound diagnostic is discussed.

[Spermatozoa antigen SAA-1 and co-precipitating molecules: regulation of human acrosome reaction]. / Spermatozoen-Antigen SAA-1 und kopräzipitierende Moleküle: Regulation der menschlichen Akrosomenreaktion.

OBJECTIVES: Examination of the regulation of the human sperm acrosome reaction as an example of ligand-induced exocytosis. METHODS: Development of monoclonal antibodies (mab) against immunaffinity-purified sperm antigen SAA-1. Examination of cross-reactivity of the mabs to human tissues using immunohistochemistry. Examination of reactivity to endometrial carcinoma cell lines and to PC-12 cells by immunohistochemistry and by radioimmunoassay. RESULTS: Mabs to immunoaffinity-purified SAA-1 recognize three coprecipitating molecules. Cross-reactivity was demonstrated to glandular epithelia exhibiting ligand-induced exocytosis, and to endometrial carcinoma and PC-12 cells. CONCLUSIONS: The proteins described could be components of the exocytosis-regulating machinery of human spermatozoa.

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study.

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1-5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5-10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information.

Channelling optics for high quality imaging of sensory hair.

A long distance microscope (LDM) is extended by a lens and aperture array. This newly formed channelling LDM is superior in high quality, high-speed imaging of large field of views (FOV). It allows imaging the same FOV like a conventional LDM, but at improved magnification. The optical design is evaluated by calculations with the ray tracing code ZEMAX. High-speed imaging of a 2 × 2 mm(2) FOV is realized at 3.000 frames per second and 1 µm per pixel image resolution. In combination with flow sensitive hair the optics forms a wall shear stress sensor. The optics images the direct vicinity of twenty-one flow sensitive hair distributed in a quadratic array. The hair consists of identical micro-pillars that are 20 µm in diameter, 390 µm in length and made from polydimethylsiloxane (PDMS). Sensor validation is conducted in the transition region of a wall jet in air. The wall shear stress is calculated from optically measured micro-pillar tip deflections. 2D wall shear stress distributions are obtained with currently highest spatiotemporal resolution. The footprint of coherent vortical structures far away from the wall is recovered in the Fourier spectrum of wall shear stress fluctuations. High energetic patterns of 2D wall shear stress distributions are identified by proper orthogonal decomposition (POD).

Cranz-Schardin camera with a large working distance for the observation of small scale high-speed flows.

The Cranz-Schardin camera utilizes a Q-switched Nd:YAG laser and four single CCD cameras. Light pulse energy in the range of 25 mJ and pulse duration of about 5 ns is provided by the laser. The laser light is converted to incoherent light by Rhodamine-B fluorescence dye in a cuvette. The laser beam coherence is intentionally broken in order to avoid speckle. Four light fibers collect the fluorescence light and are used for illumination. Different light fiber lengths enable a delay of illumination between consecutive images. The chosen interframe time is 25 ns, corresponding to 40 × 10(6) frames per second. Exemplarily, the camera is applied to observe the bow shock in front of a water jet, propagating in air at supersonic speed. The initial phase of the formation of a jet structure is recorded.