Managing menopausal symptoms and associated clinical issues in breast cancer survivors

Objective: Review evidence to guide management of menopausal signs and symptoms in women after breast cancer and make recommendations accordingly. Evidence: Randomized controlled clinical trials, observational studies, evidence-based guidelines, and expert opinion from professional societies. Background: Symptoms and clinical problems associated with estrogen depletion—sleep disorders, vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), mood changes, depressive symptoms, cardiovascular disease, osteopenia, and osteoporosis—confront the estimated 9.3 million breast cancer survivors globally. Recommendations: Following breast cancer, women should not generally be treated with menopausal hormone therapy or tibolone but should optimize lifestyle. Women with moderate to severe symptoms may benefit from mind–brain behavior or nonhormone, pharmacologic therapy. The selective serotonin/noradrenaline reuptake inhibitors and gabapentenoid agents improve VMS and quality of life. For osteoporosis, nonhormonal agents are available. Treatment of VVA remains an area of unmet need. Low-dose vaginal estrogen is absorbed in small amounts with blood levels remaining within the normal postmenopausal range but could potentially stimulate occult breast cancer cells, and although poorly studied, is not generally advised, particularly for those on aromatase inhibitors. Intravaginal dehydroepiandrosterone and oral ospemiphene have been approved to treat dyspareunia, but safety after breast cancer has not been established. Vaginal laser therapy is being used for VVA but efficacy from sham-controlled studies is lacking. Therapies undergoing development include lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol. Conclusions: Nonhormone options and therapies are available for treatment of estrogen depletion symptoms and clinical problems after a diagnosis of breast cancer. Individualization of treatment is essential

Treatment of symptoms of the menopause: an endocrine society clinical practice guideline

Objective: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. Participants: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. Evidence: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. Consensus Process: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. Conclusions: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures

Clinical, Pathological, and Surgical Outcomes for Adult Pineoblastomas

Introduction Pineoblastomas are uncommon primitive neuroectodermal tumors that occur mostly in children; they are exceedingly rare in adults. Few published reports have compared the various aspects of these tumors between adults and children. Methods The authors report a series of 12 pineoblastomas in adults from 2 institutions over 24 years. The clinical, radiologic, and pathologic features and clinical outcomes were compared with previously reported cases in children and adults. Results Patient age ranged from 24 to 81 years, and all but 1 patient exhibited symptoms of obstructive hydrocephalus. Three patients underwent gross total resection, and subtotal resection was performed in 3 patients. Diagnostic biopsy specimens were obtained in an additional 6 patients. Pathologically, the tumors had the classical morphologic and immunohistochemical features of pineoblastomas. Postoperatively, 10 patients received radiotherapy, and 5 patients received chemotherapy. Compared with previously reported cases, several differences were noted in clinical outcomes. Of the 12 patients, only 5 (42%) died of their disease (average length of survival, 118 months); 5 patients (42%) are alive with no evidence of disease (average length of follow-up, 92 months). One patient died of unrelated causes, and one was lost to follow-up. Patients with subtotal resections or diagnostic biopsies did not suffer a worse prognosis. Of the 9 patients with biopsy or subtotal resection, 4 are alive, 4 died of their disease, and 1 died of an unrelated hemorrhagic cerebral infarction. Conclusions Although this series is small, the data suggest that pineoblastomas in adults have a less aggressive clinical course than in children

Recurrent Modification of a Conserved Cis-Regulatory Element Underlies Fruit Fly Pigmentation Diversity

The development of morphological traits occurs through the collective action of networks of genes connected at the level of gene expression. As any node in a network may be a target of evolutionary change, the recurrent targeting of the same node would indicate that the path of evolution is biased for the relevant trait and network. Although examples of parallel evolution have implicated recurrent modification of the same gene and cis-regulatory element (CRE), little is known about the mutational and molecular paths of parallel CRE evolution. In Drosophila melanogaster fruit flies, the Bric-à-brac (Bab) transcription factors control the development of a suite of sexually dimorphic traits on the posterior abdomen. Female-specific Bab expression is regulated by the dimorphic element, a CRE that possesses direct inputs from body plan (ABD-B) and sex-determination (DSX) transcription factors. Here, we find that the recurrent evolutionary modification of this CRE underlies both intraspecific and interspecific variation in female pigmentation in the melanogaster species group. By reconstructing the sequence and regulatory activity of the ancestral Drosophila melanogaster dimorphic element, we demonstrate that a handful of mutations were sufficient to create independent CRE alleles with differing activities. Moreover, intraspecific and interspecific dimorphic element evolution proceeded with little to no alterations to the known body plan and sex-determination regulatory linkages. Collectively, our findings represent an example where the paths of evolution appear biased to a specific CRE, and drastic changes in function were accompanied by deep conservation of key regulatory linkages. © 2013 Rogers et al

Is children's reading “good enough”? Links between online processing and comprehension as children read syntactically ambiguous sentences

We monitored 8- and 10-year-old children’s eye movements as they read sentences containing a temporary syntactic ambiguity to obtain a detailed record of their online processing. Children showed the classic garden-path effect in online processing. Their reading was disrupted following disambiguation, relative to control sentences containing a comma to block the ambiguity, although the disruption occurred somewhat later than would be expected for mature readers. We also asked children questions to probe their comprehension of the syntactic ambiguity offline. They made more errors following ambiguous sentences than following control sentences, demonstrating that the initial incorrect parse of the garden-path sentence influenced offline comprehension. These findings are consistent with “good enough” processing effects seen in adults. While faster reading times and more regressions were generally associated with better comprehension, spending longer reading the question predicted comprehension success specifically in the ambiguous condition. This suggests that reading the question prompted children to reconstruct the sentence and engage in some form of processing, which in turn increased the likelihood of comprehension success. Older children were more sensitive to the syntactic function of commas, and, overall, they were faster and more accurate than younger children

In Defense of Competition During Syntactic Ambiguity Resolution

In a recent series of publications (Traxler et al. J Mem Lang 39:558–92, 1998; Van Gompel et al. J Mem Lang 52:284–07, 2005; see also Van Gompel et al. (In: Kennedy, et al.(eds) Reading as a perceptual process, Oxford, Elsevier pp 621–48, 2000); Van Gompel et al. J Mem Lang 45:225–58, 2001) eye tracking data are reported showing that globally ambiguous (GA) sentences are read faster than locally ambiguous (LA) counterparts. They argue that these data rule out ‘constraint-based’models where syntactic and conceptual processors operate concurrently and syntactic ambiguity resolution is accomplished by competition. Such models predict the opposite pattern of reading times. However, this argument against competition is valid only in conjunction with two standard assumptions in current constraint-based models of sentence comprehension: (1) that syntactic competitions (e.g., Which is the best attachment site of the incoming constituent?) are pooled together with conceptual competitions (e.g., Which attachment site entails the most plausible meaning?), and (2) that the duration of a competition is a function of the overall (pooled) quality score obtained by each competitor. We argue that it is not necessary to abandon competition as a successful basis for explaining parsing phenomena and that the above-mentioned reading time data can be accounted for by a parallel-interactive model with conceptual and syntactic processors that do not pool their quality scores together. Within the individual linguistic modules, decision-making can very well be competition-based

Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle

Introduction During the menstrual cycle, the mammary gland goes through sequential waves of proliferation and apoptosis. in mammary epithelial cells, hormonal and non-hormonal factors regulate apoptosis. To determine the cyclical effects of gonadal steroids on breast homeostasis, we evaluated the apoptotic index ( AI) determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ( TUNEL) staining in human mammary epithelial cells during the spontaneous menstrual cycle and correlated it with cellular proliferation as determined by the expression of Ki-67 during the same period.Methods Normal breast tissue samples were obtained from 42 randomly selected patients in the proliferative ( n = 21) and luteal ( n = 21) phases. Menstrual cycle phase characterization was based on the date of the last and subsequent menses, and on progesterone serum levels obtained at the time of biopsy.Results the proliferation index ( PI), defined as the number of Ki-67-positive nuclei per 1,000 epithelial cells, was significantly larger in the luteal phase (30.46) than in the follicular phase (13.45; P = 0.0033). the AI was defined as the number of TUNEL-positive cells per 1,000 epithelial cells. the average AI values in both phases of the menstrual cycle were not statistically significant ( P = 0.21). However, the cell renewal index ( CRI = PI/AI) was significantly higher in the luteal phase ( P = 0.033). A significant cyclical variation of PI, AI and CRI was observed. PI and AI peaks occurred on about the 24th day of the menstrual cycle, whereas the CRI reached higher values on the 28th day.Conclusions We conclude that proliferative activity is dependent mainly on hormonal fluctuations, whereas apoptotic activity is probably regulated by hormonal and non-hormonal factors.Universidade Federal de São Paulo, Dept Gyneol, Mastol Div, São Paulo, BrazilStanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USAAPC Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Gyneol, Mastol Div, São Paulo, BrazilWeb of Scienc

Flexible copyright: the law and economics of introducing an open norm in the Netherlands

This study analyses the law and economics of introducing flexibility in the system of exceptions and limitations in Dutch copyright law. Such flexibility would exist in an open norm, on the basis of which the courts can decide whether certain uses of copyrighted material are permissible or not, instead of explicitly defining this in the law. First, it assesses problem areas where the lack of flexibility creates legal disputes and potential barriers to innovation and commercialisation. Second, it analyses the economic rationale and economic effects of introducing flexibility. The study was commissioned by the Dutch Ministry of Economic Affairs, Agriculture & Innovation. Research methods used are literature review and in-depth interviews. The study includes a case study of Israel, where a fair use exception was introduced in the Copyright Act in 2007. Exceptions and limitations in the current copyright system are meant to balance the protection granted to rights owners with the public interest’s need to make certain unauthorized uses. However, this report identified a number of situations that do not fit well within the current set of exceptions and limitations and attributes this to a lack of flexibility. Among these uses are the activities of search engines, the use of works in User Created Content, cloud computing, data mining, distance learning, and transformative uses by, for instance, documentary filmmakers. Several of these problem areas have given rise to court proceedings with varying outcomes. The interpretation given by courts to existing exceptions and limitations - such as the quotation right, the exception for transient and incidental copying, the private copying exception, and the incidental use exception - is usually too narrow to respond to new technological developments, new developments in the creation process, or new commercialisation models. These types of uses generally do not ‘fit’ the narrowly defined exceptions and limitations and therefore lack legal basis. The same is true for things not yet invented. Because the law is not flexible in itself, courts have increasingly found inventive ways to create legal space for uses that are not covered by the exhaustive list of exceptions. In these cases flexibility with specific evaluation criteria could have been more satisfactory from a legal perspective. Flexibility could be obtained by introducing an open norm in the copyright system. This report defines such an open norm for the purpose of analysing the effects of more flexibility in copyright law. The norm has two main properties. First, it would coexist with the exhaustive list of exceptions and limitations in the current Dutch Copyright Act. Second, a use of a work would only benefit from the open norm if it passes the so-called three-step test, which takes the interests of the author or right holder into account. The first category of economic effects of introducing an open norm is that for some known uses that otherwise require licensing, the open norm would allow unlicensed use. Thispotentially reduces the reward to the creator of a work and therefore decreases the incentive to create. By contrast, it is also likely to reduce the creator’s costs of using another work as an input when producing a new work, and therefore to increase the incentive to create. It is difficult to predict which of these two opposing effects ultimately turns the scale in specific markets. Traditional creators generally worry about the negative effect on their reward and seem to believe that the first effect dominates. For businesses that use large numbers of protected works as an input for their services, such as Google, the opposite is true. They emphasise the benefits of reduced input costs and are likely to improve their legal position with an open norm. Collective rights management organisations in turn fear that their bargaining power vis-à-vis users like UCC-platforms, such as YouTube, would suffer from an open norm. However, given the design of the open norm, it is unlikely that rewards for creators are significantly affected. The application of the open norm by the courts tests for adverse effects on the business model of the rights holder (the previously mentioned three-step test). In case of severe adverse effects on the rights holder, the open norm does not apply. The shift in bargaining power from rights holders to user (platforms) is limited to cases that are currently licensed and where parties are sufficiently confident that the use benefits from the open norm. The second category of economic effects of introducing an open norm is that the legal delineation between infringement and permissible use becomes capable of accommodating developments in technology and society. This enables entrepreneurs to develop new products and services that rely on currently unforeseen use of protected material. On the downside, flexibility may reduce legal certainty in the short run, until jurisprudence on the practice of flexible copyright has developed. The countries that have recently introduced an open norm in their copyright laws have not produced any ex-ante or ex-post studies on the magnitude of these economic effects. The case study of fair use in Israel shows that the change may decrease legal certainty in the short run (as case law needs time to develop), but improve legal certainty in the longer run, as the legal position of acts that do not ‘fit’ a rigid system with an exhaustive list of static exceptions is being clarified. In sum, the main effects of introducing an open norm seem to be of a legal nature: it changes the legal position of some businesses and therefore affects the costs these businesses make to comply with copyright. ‘Tomorrow’s inventions’ are likely to be facilitated by an open norm. Since most businesses seem currently not chilled by the lack of flexibility, the effect on products and services available in the market is likely to be secondary to the legal effects