Therapy Insight: Parenteral Estrogen treatment for Prostate Cancer—a new dawn for an old therapy

Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers

Is there a role for chemotherapy in prostate cancer?

There is evidence from randomised-controlled trials that patients with symptomatic hormone-refractory prostate cancer may experience palliative benefit from chemotherapy with mitoxantrone and prednisone. This treatment is well tolerated, even by elderly patients, although the cumulative dose of mitoxantrone is limited by cardiotoxicity. Treatment with docetaxel or paclitaxel, with or without estramustine, appears to convey higher rates of prostate-specific antigen response in phase II trials, but is more toxic. Large phase III trials comparing docetaxel with mitoxantrone have completed accrual. There is no role for chemotherapy in earlier stages of disease except in the context of a well-designed clinical trial

The Real maccoyii: Identifying Tuna Sushi with DNA Barcodes – Contrasting Characteristic Attributes and Genetic Distances

BACKGROUND:The use of DNA barcodes for the identification of described species is one of the least controversial and most promising applications of barcoding. There is no consensus, however, as to what constitutes an appropriate identification standard and most barcoding efforts simply attempt to pair a query sequence with reference sequences and deem identification successful if it falls within the bounds of some pre-established cutoffs using genetic distance. Since the Renaissance, however, most biological classification schemes have relied on the use of diagnostic characters to identify and place species. METHODOLOGY/PRINCIPAL FINDINGS:Here we developed a cytochrome c oxidase subunit I character-based key for the identification of all tuna species of the genus Thunnus, and compared its performance with distance-based measures for identification of 68 samples of tuna sushi purchased from 31 restaurants in Manhattan (New York City) and Denver, Colorado. Both the character-based key and GenBank BLAST successfully identified 100% of the tuna samples, while the Barcode of Life Database (BOLD) as well as genetic distance thresholds, and neighbor-joining phylogenetic tree building performed poorly in terms of species identification. A piece of tuna sushi has the potential to be an endangered species, a fraud, or a health hazard. All three of these cases were uncovered in this study. Nineteen restaurant establishments were unable to clarify or misrepresented what species they sold. Five out of nine samples sold as a variant of "white tuna" were not albacore (T. alalunga), but escolar (Lepidocybium flavorunneum), a gempylid species banned for sale in Italy and Japan due to health concerns. Nineteen samples were northern bluefin tuna (T. thynnus) or the critically endangered southern bluefin tuna (T. maccoyii), though nine restaurants that sold these species did not state these species on their menus. CONCLUSIONS/SIGNIFICANCE:The Convention on International Trade Endangered Species (CITES) requires that listed species must be identifiable in trade. This research fulfills this requirement for tuna, and supports the nomination of northern bluefin tuna for CITES listing in 2010

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions

Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial

Background: The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases.Methods: STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously.Results: The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity.Conclusion: It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies

Bladder cancer in the elderly patient: challenges and solutions

Elizabeth A Guancial,1 Breton Roussel,2 Derek P Bergsma,3 Kevin C Bylund,3 Deepak Sahasrabudhe,1 Edward Messing,4 Supriya G Mohile,1 Chunkit Fung1 1Division of Hematology/Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center School of Medicine and Dentistry, Rochester, NY, 2Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 3Department of Radiation Oncology, Wilmot Cancer Institute, University of Rochester, Rochester, NY, 4Department of Urology, University of Rochester, Rochester, NY, USA Abstract: Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC. Keywords: bladder cancer, elderly, quality of life, surgery, radiation therapy, chemotherap