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.

Hepatitis E virus seroprevalence, seroincidence and seroreversion in the German adult population.

A steep rise in Hepatitis E diagnoses is currently being observed in Germany and other European countries. The objective of this study was (i) to assess whether this trend mirrors an increase in infection pressure or is caused by increased attention and testing and (ii) estimate individual and population-based Hepatitis E Virus (HEV) seroconversion and seroreversion rates for Germany. We measured anti-HEV IgG prevalence in 10 407 adults participating in two linked, population-representative serosurveys (total n = 12 971) conducted in 1998 and 2010. In this period, we found a moderate but statistically significant decline of overall anti-HEV IgG prevalence from 18.6% to 15.3%. At both time points, seroprevalence increased with age and peaked in persons born between 1935 and 1959 suggesting a past period of increased infection pressure. Paired samples of individuals participating in 1998 and 2010 (n = 2564) revealed respective seroconversion and seroreversion rates of 6.2% and 22.6% among seronegative and seropositive individuals during 12 years, or 5.2 and 2.9 per 1000 inhabitants per year. This corresponds to a total of 417 242 [95%CI: 344 363-495 971] new seroconversions per year in the German population. While anti-HEV seroprevalence has decreased in the last decade, infection pressure and seroincidence remains high in Germany. Continuously rising numbers of Hepatitis E diagnoses in Europe are likely due to an increased awareness of clinicians and indicate that still there is a gap between incident and diagnosed cases. Studies on the true burden of the disease, specific risk factors and sources of autochthonous infections as well as targeted prevention measures are urgently needed.

Time course of hepatitis E-specific antibodies in adults.

Hepatitis E virus (HEV) is highly endemic in industrialized countries, but there is a lack of knowledge on individual and overall antibody concentration dynamics. The aim of this study was to characterize longitudinal concentration changes of anti-HEV immunoglobulin G (anti-HEV IgG) by enzyme immunoassay (EIA). In total, 199 serum samples collected from 45 subjects over 18 years were analysed. A wide range of anti-HEV IgG levels was found. Overall, anti-HEV IgG significantly decreased after an observation period of at least 5 years. One negative seroconversion was observed. Four individual profiles suggested single and even multiple HEV reinfections despite pre-existing HEV antibodies.

Ultrasound elastography of pulmonary lesions - a feasibility study.

INTRODUCTION: The potential of sonography in the examination of lung tissue is extremely limited by the air-filled alveoles of the lung. Only in special circumstances like pleural adhesion lesions, atelectasis or pneumonia can lung tissue be visualized by B-mode sonography. Real-time elastography was primarily applied to detect and visualize pulmonary lesions. METHODS AND PATIENTS: 8 patients with a total of 18 histologically proven metastases of the lung were included. All pulmonary lesions were detected by computed tomography. Sonographic examination was performed with a 7.5 MHz linear transducer (Acuson Antares premium edition, Siemens, Erlangen, Germany), including B-mode and real-time elastography (RTE). The mean distance between pleura and the lesions ranged from 0 to 2.5 cm. Two lesions were located in the upper right lobe, eleven lesions in the lower right and five in the lower left lobe. RESULTS: RTE was able to detect and visualize all 18 pulmonary lesions in contrast to B-mode. The size and distance of the lesions from the pleura correlated with the CT findings. CONCLUSION: In contrast to B-mode sonography, RTE is able to detect and visualize peripheral, non-pleural adherent pulmonary lesions.

[Future of mammography-based imaging]. / Zukunft mammographiebasierter Bildgebung.

Mammography is the central diagnostic method for clinical diagnostics of breast cancer and the breast cancer screening program. In the clinical routine complementary methods, such as ultrasound, tomosynthesis and optional magnetic resonance imaging (MRI) are already combined for the diagnostic procedure. Future developments will utilize investigative procedures either as a hybrid (combination of several different imaging modalities in one instrument) or as a fusion method (the technical fusion of two or more of these methods) to implement fusion imaging into diagnostic algorithms. For screening there are reasonable hypotheses to aim for studies that individualize the diagnostic process within the screening procedure. Individual breast cancer risk prediction and individualized knowledge about sensitivity and specificity for certain diagnostic methods could be tested. The clinical implementation of these algorithms is not yet in sight.

[Sebaceous breast carcinoma: report of a rare histological special subtype]. / Sebaziöses Mammakarzinom: Fallbericht eines seltenen speziellen Subtyps.

We report on a case of sebaceous carcinoma of the breast as a rare histological special subtype of breast cancer. Because these tumors are uncommon, differential diagnostic considerations and the exclusion of Muir-Torre syndrome are emphasized. Finally possible mechanisms of development and therapeutic strategies for this carcinoma are discussed.

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.

Evaluation of a Marker Clip System in Sonographically Guided Core Needle Biopsy for Breast Cancer Localization Before and After Neoadjuvant Chemotherapy.

Introduction The placement of intramammary marker clips has proven to be helpful for tumor localization in patients undergoing neoadjuvant chemotherapy and breast-conserving surgery. The purpose of our study was to investigate the feasibility of using a clip marker system for breast cancer localization and its influence on the imaging assessment of treatment responses after neoadjuvant chemotherapy. Patients and Methods Between March and June 2015, a total of 25 patients (n = 25), with a suspicion of invasive breast cancer with diameters of at least 2 cm (cT2), underwent preoperative sonographically guided core needle biopsy using a single-use breast biopsy system (HistoCore™) and intramammary clip marking using a directly adapted clip system based on the established O-Twist Marker™, before their scheduled preoperative neoadjuvant chemotherapy. Localization of the intramammary marker clip was controlled by sonography and digital breast tomosynthesis. Results Sonography detected no dislocation of intrammammary marker clips in 20 of 25 patients (80 %), while digital breast tomosynthesis showed accurate placement without dislocation in 24 patients (96 %) (p < 0.05). There was no evidence of significant clip migration during preoperative follow-up imaging after neoadjuvant chemotherapy. No complication related to the clip marking was noted and there was no difficulty in evaluating the treatment response to neoadjuvant chemotherapy. Among the breast-conserving surgeries performed, no cases were identified in which intraoperative loss of the marker clip had occurred. Conclusion Our study underscores the importance of intramammary marking clip systems before neoadjuvant chemotherapy. Placement of marker clips is advised to facilitate accurate tumor bed localization. With regard to digital breast tomosynthesis, its development continues to improve the quality of diagnostics and the therapy of breast cancer particularly for small breast cancer tumors or in neoadjuvant chemotherapy setting.

Touch Imprint Cytology and Stereotactically-Guided Core Needle Biopsy of Suspicious Breast Lesions: 15-Year Follow-up.

Introduction: Stereotactically-guided core needle biopsies (CNB) of breast tumours allow histological examination of the tumour without surgery. Touch imprint cytology (TIC) of CNB promises to be useful in providing same-day diagnosis for counselling purposes and for planning future surgery. Having addressed the issue of accuracy of immediate microscopic evaluation of TIC, we wanted to re-examine the usefulness of this procedure in light of the present health care climate of cost containment by incorporating the surgical 15-year follow-up data and outcome. Patients and Methods: From January until December 1996 we performed TIC in core needle biopsies of 173 breast tumours in 169 patients, consisting of 122 malignant and 51 benign tumours. Histology of core needle biopsies was proven by surgical histology in all malignant and in 5 benign tumours. Surgical breast biopsy was not performed in 46 patients with 46 benign lesions, as the histological result from the core needle biopsy and the result of the TIC were in agreement with the suspected diagnosis from the complementary breast diagnostics. A 15-year follow-up of these patients followed in 2013 and follow-up data was collected from 40 women. Results: In the 15-year follow-up of the 40 benign lesions primarily confirmed using CNB and TIC, a diagnostic sensitivity, specificity, positive and negative predictive value and accuracy of 100 % was found. Conclusion: TIC and stereotactically guided CNB showed excellent long-term follow-up in patients with benign breast lesions. The use of TIC to complement CNB can therefore provide immediate cytological diagnosis of breast lesions.

Comparison of Sonography versus Digital Breast Tomosynthesis to Locate Intramammary Marker Clips.

Introduction: This study aimed to compare the accuracy of sonography versus digital breast tomosynthesis to locate intramammary marker clips placed under ultrasound guidance. Patients and Methods: Fifty patients with suspicion of breast cancer (lesion diameter less than 2 cm [cT1]) had ultrasound-guided core needle biopsy with placement of a marker clip in the center of the tumor. Intramammary marker clips were subsequently located with both sonography and digital breast tomosynthesis. Results: Sonography detected no dislocation of intrammammary marker clips in 42 of 50 patients (84 %); dislocation was reported in 8 patients (16 %) with a maximum dislocation of 7 mm along the x-, y- or z-axis. Digital breast tomosynthesis showed accurate placement without dislocation of the intramammary marker clip in 48 patients (96 %); 2 patients (4 %) had a maximum clip dislocation of 3 mm along the x-, y- or z-axis (p < 0.05). Conclusion: The use of digital breast tomosynthesis could improve the accuracy when locating intramammary marker clips compared to sonography and could, in future, be used to complement or even completely replace sonography.

Hormone Therapy and its Effect on the Prognosis in Breast Cancer Patients.

Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.

Neuropeptide Y stimulates inositol phospholipid hydrolysis in rat brain miniprisms.

Neuropeptide Y (NPY) stimulates the hydrolysis of inositol phospholipid in rat brain miniprisms. The stimulation was two-fold in the frontal cortex and in the hippocampus, and 1.5-fold in the striatum. NPY produced no significant effects on basal inositol monophosphate levels in hypothalamic miniprisms. However, those basal levels were much higher than in the other brain regions.

3H-Spiroperidol binding to dopamine receptors in rat striatal membranes: influence of loxapine and its hydroxylated metabolites.

The effects of loxapine and its hydroxylated metabolites 7-hydroxyloxapine and 8-hydroxyloxapine on 3H-spiroperidol binding to rat striatal membranes were investigated. Whereas 7-hydroxyloxapine and loxapine displayed strong affinities for 3H-spiroperidol binding sites, 8-hydroxyloxapine was essentially inactive. The potency of 7-hydroxyloxapine to displace 3H-spiroperidol is 1.5 times and 8 times those of haloperidol and chlorpromazine, respectively. These results suggest that the combined effects of loxapine and 7-hydroxyloxapine on the postsynaptic dopamine receptors in the brain may explain the clinical efficacy of loxapine in the treatment of schizophrenia.

Interaction of amoxapine with muscarinic cholinergic receptors: an in vitro assessment.

Amoxapine, an antidepressant with a rapid onset of therapeutic efficacy and great utility in psychotic depression, has been reported to produce anticholinergic side effects in man similar to those observed with imipramine and amitriptyline. To establish its cholinergic disposition, amoxapine and its metabolites 7-hydroxyamoxapine and 8-hydroxyamoxapine, have been evaluated by determining their effects on quinuclidinyl benzilate (QNB) binding to membrane fractions of rat and human brain, on the carbamoylcholine-stimulated accumulation of inositol phosphates in rat cerebral cortex and on the acetylcholine-induced contraction of the guinea pig ileum. In all three preparations, amoxapine was found to be a considerably weaker antagonist of muscarinic cholinergic receptors than either imipramine (4-27 fold) or amitriptyline (51-300 fold). These results indicate that for amoxapine, no correlation exists between the magnitude of muscarinic receptor inhibition and the extent of 'anticholinergic' side effects found in the clinic. Neither the metabolites of amoxapine nor species differences could account for this discrepancy.

The effects of acute administration of diazepam on the binding of [3H]-diazepam and [3H]-gaba to rat cortical membranes.

Specific [3H]-diazepam binding and [3H]-GABA binding were measured in cortical membranes of untreated rats and rats which had been administered unlabeled diazepam (5.0 mg/kg, IP) thirty minutes prior to sacrifice. Washed and unwashed membranes from control animals showed identical levels of [3H]-diazepam binding. Unwashed membranes of diazepam-treated animals showed consistently and significantly lower binding of [3H]-diazepam than membranes derived from control animals and treated similarly. [3H]-GABA was almost non-existent in unwashed membranes of either group of animals. The binding capability of membranes of treated animals for [3H]-diazepam returned to control levels upon washing with buffer prior to the binding assay. The specific binding of [3H]-GABA in membranes derived from either group of animals also improved after the buffer washes. However, no difference could be detected in [3H]-GABA binding between control and diazepam-treated animals. The failure of diazepam to modulate [3H]-GABA binding in unwashed membranes and the participation of an endogenous inhibitory material repressing [3H]-GABA binding are discussed.

Striatally-mediated response of some structurally rigid analogues of dopamine.

The potency of structurally rigid analogues of dopamine (DA) at striatal dopamine receptors was evaluated in rats using three types of assessments: (a) effectiveness in producing rotational and sniffing behaviors by intrastriatal injections (b) inhibition of [3H]-spiroperidol binding and (c) stimulation of adenylate cyclase activity. The compounds included apomorphine (APO) and its analogues, (R)-2,10,11-trihydroxyaporphine (R-THA) and (R)-2-hydroxy-10,11-methylenedioxyaporphine (MDO-APO), 2-amino-6,7-dihydroxyaminotetraline (ADTN) and its analogue, exo-2-amino-6,7-dihydroxybenzonorbornene (exo-amine). (R)-THA produced no stereotypy yet it was a potent inhibitor of [3H]-spiroperidol binding and adenylate cyclase activity. MDO-APO was quite active in inducing stereotypy and stimulating cyclase activity, but it showed low potency in displacing [3H]-spiroperidol. The exo-amine and ADTN were equally potent in enhancing rotation and sniffing intensity, however, the former was completely inactive in biochemical assessments. Except for (R)-THA, all DA analogues studied elicited dopaminomimetic behavioral activities of circling and sniffing. Relationships between the actions of these drugs in the behavioral and biochemical assessments are discussed.

Human brain receptor alterations in suicide victims.

A comparison was made of human postmortem muscarinic-cholinergic, beta-adrenergic and serotonergic (presynaptic) recognition sites in cortical tissues derived from suicide and homicide (control) victims. An elevation of 47% and 35% in the suicide group compared to controls was observed in receptor ligand binding for 3H-quinuclidinyl benzilate (QNB, muscarinic antagonist) and 3H-imipramine (IMI, a presynaptic serotonin marker), respectively. In contrast, no appreciable differences in 3H-dihydroalprenolol (DHA, beta-adrenergic antagonist) binding were observed between the two groups. Additionally, tissues from both groups of subjects were analyzed for tricyclic antidepressive agent (TAD) content. High performance liquid chromatographic (HPLC) tissue analysis revealed no detectable levels of tricyclic agents with an assay sensitivity of 50 picograms/mg tissue. The results presented herein demonstrate neurotransmitter-receptor alterations in suicide subjects compared to homicide (control) victims. The attendant roles of serotonergic and muscarinic-cholinergic processes in the psychobiology of suicide and depression are addressed.

Time and Resources Needed to Document Patients with Breast Cancer from Primary Diagnosis to Follow-up - Results of a Single-center Study.

Aim: Certification of breast centers helps improve the quality of care but requires additional resources, particularly for documentation. There are currently no published data on the actual staff costs and financial resources required for such documentation. The aim of this study was to determine the time and resources required to document a patient with primary breast cancer from diagnosis to the end of follow-up, to establish a database for future strategic decisions. Material and Methods: All diagnostic and therapeutic procedures of patients with primary breast cancer were recorded at the University Breast Center of Franconia. All time points for documentation were evaluated using structured interviews. The times required to document a representative number of patients were determined and combined with the staff costs of the different professional groups, to calculate the financial resources required for documentation. Results: A total of 494 time points for documentation were identified. The study also identified 21 departments and 20 different professional groups involved in the documentation. The majority (54 %) of documentation was done by physicians. 62 % of all documentation involved outpatients. The results of different scenarios for the diagnosis, therapy and follow-up of breast cancer patients in a certified breast center showed that the time required for documentation can be as much as 105 hours, costing € 4135. Conclusion: This analysis shows the substantial staffing and financial costs required for documentation in certified centers. A multi-center study will be carried out to compare the costs for certified breast centers of varying sizes with the costs of non-certified care facilities.

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.

Evaluation of Newly Adapted Clip Marker System in Ultrasound-Guided Core Needle Biopsy for Suspicion of Breast Cancer.

Introduction: A newly adapted clip system for intramammary marking during ultrasound-guided core needle biopsy for suspicion of breast cancer is described and evaluated here. Material and Method: Fifty patients with suspicion of breast cancer (cT2) had ultrasound-guided core needle biopsy using a newly adapted clip marker system (HistoCore™ and O-Twist Marker™). Subsequently, ultrasound follow-up and tomosynthesis scans were done to determine the location of the marker clips. Results: No dislocation of the marker clip was detected on ultrasound in 45 of 50 patients (90 %), and 5 patients (10 %) had a maximum dislocation of 5 mm along the x-, y- or z-axis. Tomosynthesis scans demonstrated precise placement without dislocation of the clip markers in 48 patients (96 %); 2 patients (4 %) had a maximum dislocation of 3 mm along the x-, y- or z-axis. Conclusion: The newly developed clip marker system, a combination of a single-use breast biopsy needle and a precise, length-adapted intramammary marker clip, represents a further improvement in oncological therapy. This is of particular importance for patients requiring subsequent neoadjuvant chemotherapy, as in cases with complete tumour remission, there is no target point for preoperative, ultrasound-guided wire marking.