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.

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.

[Current Perceptions of Lipofilling on the Basis of the New Guideline on "Autologous Fat Grafting"]. / Aktuelle Erkenntnisse zur Eigenfett Transplantation anhand der neuen Leitlinie "Autologe Fetttransplantation".

Introduction: Autologous fat transfer has recently become an increasingly popular surgical procedure and comprises harvesting, processing and transplantation of adipose tissue, as well as professional follow-up care. This method, as a surgical procedure, can be utilised for trauma-, disease- or age-related soft tissue volume deficits and soft tissue augmentation. As usage is increasing, but the variables of fat harvest, specific indications and fashion of fat transfer are poorly defined, there is a great demand for development of a guideline in the field of reconstructive and aesthetic surgery. Methods: All relevant points were discussed within the scope of a consensus conference including a nominal group process of all societies involved in the procedure and ratified with a strong consensus (>95%). Literature from the standard medical databases over the last 10 years was retrieved, studied and specific guidelines were concluded. Results: Consensus was achieved among all professionals involved on the following points: 1. definition 2. indication/contraindication, 3. preoperative measures 4. donor sites 5. techniques of processing 6. transplantation 7. follow-up care 8. storage 9. efficacy 10. documentation 11. evaluation of patient safety. Conclusion: Definite indications and professional expertise are paramount for autologous fat tissue transfer. Successful transfers are based on the use of correct methods as well as specific instruments and materials. Autologous adipose tissue transplantation is considered to be a safe procedure in reconstructive and aesthetic surgery, due to the low rate of postoperative complications and sequelae.

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.

Breast preservation versus mastectomy--recurrence and survival rates of primary breast cancer patients treated at the UFK Bonn.

The aim of this retrospective long-term analysis was to evaluate the approach of breast conservation in the light of the results obtained, on the basis of mastectomy, in patients with early breast carcinoma. Additionally, the effect of internal mammary and supraclavicular radiotherapy was analyzed. Therefore, local-regional recurrence (LRR) and survival rates were examined in 411 patients with T1 and T2 stages who had undergone either breast-preserving surgery with radiation or mastectomy. Individual risk factors such as nodal status, lymphangiosis carcinomatosa and age of the patients were evaluated, too. The rate of local-regional recurrence in patients who were treated by mastectomy and conservative surgery was 9.2% and 11.0%, respectively, with relapse happening earlier in the latter group (median of 16 vs. 24 months). Survival rates, however, were not different in the two groups. Tumour stage and nodal status had no influence on the local-regional recurrence rate in either group. In connection with lymphangiosis carcinomatosa, however, the rate increased to 14.5% (mastectomy) and 19.0% (breast-preserving surgery), respectively. Patients < or = 40 years had an even higher risk of LRR, with 20.6% when they underwent mastectomy and 30.8% following breast conservation. Internal mammary and supraclavicular radiotherapy had no positive effect on the survival rates, neither in the mastectomy nor in the breast conservation group. As a conclusion, in more than 60% of all T1 stages. and more than 50% of all T2 stages, the therapeutic concept of breast preservation seems to be justified.

Electroencephalographic correlates of periventricular white matter lesions in probable Alzheimer's disease.

We evaluated the relationship between periventricular white matter lesions (PWMLs) and EEG abnormalities in probable Alzheimer's disease (AD). We visually analyzed the EEG of 27 probable AD patients with mild to moderate degree of cognitive impairment participating in a longitudinal study of dementia. Patients had both CT and MRI scans performed at baseline examination, which also included an EEG. PWMLs were rated in CT and MRI films using a semiquantitative method. The EEGs were classified according to the Mayo Clinic Classification System. Abnormal EEGs correlated with PWMLs rating scores were detected on CT, but not on MRI. These data suggest that the presence of PWMLs contribute to the abnormal EEGs observed in AD patients, and that white matter abnormalities in CT correlate better with both the clinical findings and EEG than does the more sensitive but less specific MRI.

Computed tomography--but not magnetic resonance imaging--identified periventricular white-matter lesions predict symptomatic cerebrovascular disease in probable Alzheimer's disease.

OBJECTIVE: To examine the clinical consequences of periventricular white-matter lesions on computed tomography (CT) and magnetic resonance imaging (MRI) scans in probable Alzheimer's disease. DESIGN: Case series, 12-month follow-up. SETTING: Multidisciplinary behavioral neurology research clinic. PATIENTS: We longitudinally evaluated the clinical characteristics of 27 patients with probable AD for whom both CT and MRI scans had been performed at baseline. INTERVENTIONS: None. MAIN OUTCOME MEASURE: The presence of abnormal neurological signs was examined at baseline and at a 12-month examination. RESULTS: Periventricular white-matter lesions were observed with CT in 12 patients (44%) and with MRI in 21 patients (78%). Computed tomography did not detect lesions of 1 to 3 mm, as were seen on MRI scans, and CT also did not detect lesions of 4 to 10 mm when they occurred in the deep subcortical white matter and were not part of a greater confluent lesion. There was no relationship between the severity of periventricular white-matter lesions with either neuroimaging method and the presence of abnormal neurological signs. However, there was a greater frequency of periventricular white-matter lesions shown on CT scans than on MRI scans at baseline in patients in whom abnormal neurological signs (eg, abnormal gait, asymmetric deep tendon reflexes, focal motor deficits, abnormal plantar response) developed at 12-month follow-up. CONCLUSION: Although MRI may be more sensitive in detecting periventricular white-matter lesions, CT is more specific in predicting subsequent symptomatic cerebrovascular disease.

Reliability of NINDS-AIREN clinical criteria for the diagnosis of vascular dementia.

We evaluated the reliability of clinical diagnoses using the recently standardized criteria for the diagnosis of vascular dementia (VaD) developed by the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN). Two neurologists and two psychiatrists independently reviewed clinical data abstracted from those of 42 demented subjects participating in a longitudinal study of dementia at the University of Pittsburgh. For each patient we abstracted the clinical data on a standardized form. Each physician diagnosed each case according to the NINDS-AIREN criteria, using both clinical information and MRIs. We calculated the interrater agreement for all two-way combinations of clinicians with kappa statistics, which ranged from 0.46 (moderate agreement) to 0.72 (substantial agreement). The moderate reliability observed in this study may be attributable to patient-, clinician-, or criteria-centered sources of variance.

Neuropsychiatric correlates of cerebral white-matter radiolucencies in probable Alzheimer's disease.

We evaluated the neuropsychological functions, rate of disease progression, and psychiatric characteristics of 22 patients with probable Alzheimer's disease in whom periventricular white-matter radiolucencies (PWMRs) were seen on the computed tomographic scan of the brain and compared them with 22 matched patients with Alzheimer's disease without PWMRs. Executive/attention, lexical/semantic, memory/learning, and visuospatial functions did not differ between the two groups at baseline or at the 1-year follow-up examination. The frequency of major depression, delusions, and hallucinations did not differ between the groups. However, patients with PWMRs had significantly higher Hachinski Rating scores at both visits and were more likely to develop cerebrovascular disease during follow-up than were controls with Alzheimer's disease. These preliminary results suggest that the presence of PWMRs is not associated with specific cognitive and psychiatric features or with an altered rate of progression of Alzheimer's disease but does predict the development of clinically significant cerebrovascular disease.

Serum autoantibodies in patients with Alzheimer's disease and vascular dementia and in nondemented control subjects.

BACKGROUND AND PURPOSE: In this study we sought to evaluate the clinical significance of serum autoantibodies to dementing processes. METHODS: We assessed 40 age-matched subjects: 10 patients with probable Alzheimer's disease, 10 with possible Alzheimer's disease with cerebrovascular disease, 10 with vascular dementia, and 10 nondemented control subjects. Serum from each subject was tested for the presence of antithyroglobulin antibody, thyroid antimicrosomal antibody, gastric anti-parietal cell antibody, anti-smooth muscle antibody, antinuclear antibody, rheumatoid factor, antineuronal antibody, and anticardiolipin antibody. In addition, we investigated the sera of these patients for the presence of an antivascular antibody directed against the vascular basement membrane proteoglycan antigen and for circulating immune complexes. RESULTS: Autoantibodies were present in 100% of the patients with possible Alzheimer's disease with cerebrovascular disease, 80% of those with vascular dementia, 40% of those with probable Alzheimer's disease, and 30% of the nondemented control subjects. The highest number of autoantibodies was observed in patients with vascular dementia and possible Alzheimer's disease with cerebrovascular disease. Antinuclear antibody was present in 60% of vascular dementia patients and antineuronal antibody in 50% of these patients. However, no individual autoantibody could differentiate Alzheimer's disease from cerebrovascular disorders. Immune complexes were detected in the serum of 20-30% of each patient group. Neither the patient nor the control sera was found to contain antiendothelial antibody. CONCLUSIONS: Despite the relatively small number of individuals examined in each category, the elevated number of autoantibodies associated with possible Alzheimer's disease with cerebrovascular disease and vascular dementia indicates a possible link between the presence of autoantibodies and cerebrovascular disorders in dementia.

Reliability of NINCDS-ADRDA clinical criteria for the diagnosis of Alzheimer's disease.

Although the NINCDS-ADRDA Work Group has recently developed uniform clinical criteria for the diagnosis of Alzheimer's disease (AD), inter-rater reliability studies of these criteria are few. We report a study in which 2 neurologists and 2 psychiatrists independently reviewed clinical data abstracted from the records of 30 demented subjects and 10 nondemented control subjects participating in a longitudinal study of AD at the University of Pittsburgh. We recorded the clinical data on a standardized form; the subjects' identity and clinical and pathologic diagnoses were omitted. Each physician diagnosed each case according to the NINCDS-ADRDA criteria. We calculated the inter-rater agreement for all possible 2-way combinations of clinicians with the Kappa statistic, which ranged from 0.36 (fair agreement) to 0.65 (substantial agreement). We conclude that current NINCDS-ADRDA criteria enable moderate levels of agreement among clinicians in general.

Olfactory deficits as a neurologic sign in dementia of the Alzheimer type.

Many patients with dementia of the Alzheimer type (DAT) have an abnormal sense of smell. I studied 18 mildly demented subjects with DAT between the ages of 60 and 80 years and found them less able to identify five fragrances compared with 26 healthy elderly controls. The mean (+/- SEM) olfactory identification score for demented subjects was 0.3 +/- 0.2 compared with 2.8 +/- 0.2 for controls. When the subjects were given a multiple-choice list of ten items including the test fragrances and five other odors, performance of both demented and normal subjects improved, with a score of 1.8 +/- 0.4 for subjects with DAT and 4.2 +/- 0.2 for controls. The findings suggest that olfactory deficits are a sensitive, although non-specific, indicator of mild DAT.

Periventricular white matter lucencies in senile dementia of the Alzheimer type and in normal aging.

The significance of periventricular lucencies in the white matter on CT in demented patients is not understood. We studied the relationship of these changes to mental status of subjects with senile dementia of the Alzheimer type. A semiquantitative method showed more numerous and extensive lucencies in demented than in healthy elderly. Neuropathologic examination of five subjects with these changes and confirmed Alzheimer's disease revealed diffuse white matter pallor without infarction. There were no hypertensive vascular changes, although limited hyaline thickening was present.

Depletion of brain mitochondria cytochrome oxidase in the mottled mouse mutant.

The mouse mutant Mobr is an animal model of Menkes kinky hair syndrome with a similar defect in copper utilization. The copper-dependent enzyme, cytochrome oxidase from the brain, liver, and heart mitochondria was examined. The brain and heart from Mobr/y had significantly less cytochrome alpha + alpha 3 than normal animals' when the cytochrome absorption spectra of tissue samples from animals 11 to 13 days of age were analyzed. Liver cytochrome was not significantly different. When brain mitochondrial cytochrome oxidase spectrograms from animals of different ages were examined, a major change was found to occur during the 2nd week of life. When cytochrome oxidase activity from brain mitochondria was measured, assaying the rate of oxidation of cytochrome c, the results were similar to those from spectrogram analysis.

Male rat brain androgen metabolism and sexual behavior.

Four groups of male rats, previously treated for sexual behavior and differing in age and length of time following castration, were examined for the localization of (3H)-testosterone (T) and (3H)-5alpha-dihydrotestosterone (DHT) in the brain following the injection of (3H)-T. Significant differences existed in the concentration of the 2 androgens among brain regions in all groups. Only in the subcellular particulate fraction from the hypothalami of 1 group castrated for 48 h was there a significant correlation (r=-0.97) between DHT and T levels and pretest mating performance. Though the amount of DHT found in the pituitary was strongly affected by the length of time between castration and sacrifice, no similar effect was found in the brain.