By O. Milten. Rhode Island School of Design.

Small-molecule FLT3 inhibitors have emerged available in 10 patients rocaltrol 0.25mcg generic, with 6 of them revealing an investigator- as an attractive therapeutic option in patients with FLT3 mutations assessed objective response (CR generic rocaltrol 0.25 mcg line, n 3; CR with incomplete (Table 3). First-generation compounds such as midostaurin platelet recovery, n 2; partial response, n 1). The data on the (PKC412), lestaurtinib (CEP-701), sunitinib (SU-11248), and efficacy of the compound did hold up in the update presented at sorafenib (BAY-43-9006), as well as second-generation agents EHA 2014. Consistent with preclinical models, marked differentia- such as quizartinib (AC220) and crenolanib, are already being tion of myeloblasts into mature forms was associated with response. When used as single agents, they have limited antileukemic activity, mostly showing MLL-rearranged AML and DOT1L inhibition. Deregulation in only transient reduction of blood and BM blasts; first randomized several epigenetic regulators that modify DNA or histones have trials evaluating these agents have been disappointing. Polo-like kinases (Plks) are a family of 5 highly conserved serine/threonine protein kinases that have been shown to The second-generation compounds such as quizartinib have im- play a key role in mitotic checkpoint regulation and cell division. This is associated with higher rates Plk1 is overexpressed in a range of human cancers, including of BM blast clearance, however, mostly without achieving formal AML. In addition, response duration is limited by the development of competitive kinase inhibitor that potently inhibits Plk1. Crenolanib is another highly selective ineligible for intensive therapy, the combination therapy doubled and potent FLT3 inhibitor exhibiting strong activity against FLT3- the response rate and even showed a signal for a survival benefit. Phase 2 trials are ongoing A pivotal placebo-controlled phase 3 trial in this patient population (www. In fully transformed cells with endogenous BET inhibition. Further therapeutic targets of potential relevance IDH1 mutations, the selective R132H-IDH1 inhibitor AGI-5198 in AML are represented by the bromodomain and extraterminal showed a near-complete R-2HG inhibition. Preclinical data in AML suggest efficacy primary IDH2 R140 AML cells with the small molecule AGI-6780, of BET inhibition across several AML subtypes. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence A new era of clinical research in AML has been entered. With the of relapse, and overall survival in adult patients with de novo acute rapid development in novel genomics technologies, comprehensive myeloid leukemia: results from Cancer and Leukemia Group B (CALGB molecular profiling will now become integral part of our clinical 8461). Molecular profiling will move away from the analysis of 5. Refinement of cytogenetic more precise diagnosis and the identification of patient subsets with classification in acute myeloid leukemia: determination of prognostic distinct gene signatures, particularly among patients with intermedi- significance of rare recurring chromosomal abnormalities among 5876 ate-risk cytogenetics. Such an integrative mutational analysis will younger adult patients treated in the United Kingdom Medical Research be instrumental to identifying patients who will benefit from novel Council trials. Genomic and epigenomic rapid progress will only be achieved if the physicians caring for landscapes of adult de novo acute myeloid leukemia. Wouters BJ, Lo¨wenberg B, Erpelinck-Verschueren CA, et al. Double recommended to further specify the intermediate-risk AML group CEBPA mutations, but not single CEBPA mutations, define a subgroup as defined by cytogenetics and to guide treatment decisions. BM of acute myeloid leukemia with a distinctive gene expression profile that aspirates should been preferentially used for the molecular analyses; is uniquely associated with a favorable outcome. Acute myeloid leukemia proportion of circulating blasts. In NPM1-mutated AML, minimal with biallelic CEBPA gene mutations and normal karyotype represents a residual disease monitoring is clinically relevant because NPM1 distinct genetic entity associated with a favorable clinical outcome. Prognostic significance of CEBPA patients at a high risk of relapse. Applicability of NPM1 minimal mutations in a large cohort of younger adult patients with acute myeloid residual disease monitoring for preemptive therapy is currently leukemia: impact of double CEBPA mutations and the interaction with under investigation. Diagnostic testing for other molecular markers FLT3 and NPM1 mutations. However, it is likely that the accumulating concurrent genetic mutations, and gene expression features of AML data on the novel molecular markers will affect upcoming revisions with CEBPA mutations in a cohort of 1182 cytogenetically normal of risk classification systems. A better understanding of the role of AML patients: further evidence for CEBPA double mutant AML as a these molecular lesions in AML biology will hopefully result in the distinctive disease entity. Prognostic relevance of clinical outcome for our AML patients. Cytoplasmic nucleophosmin in acute myelogenous This work was supported in part by Grant BU 1339/5-1 from the leukemia with a normal karyotype. Deutsche Forschungsgemeinschaft and Grant 109675 by the Deut- 13. We thank Daniela Spa¨th for support with creating (NPM1) predicts favorable prognosis in younger adults with acute the figures in this manuscript and Hartmut Do¨hner for critically myeloid leukemia and normal cytogenetics: interaction with other gene reviewing the manuscript. Mutations and treatment Disclosures outcome in cytogenetically normal acute myeloid leukemia. Age-related risk profile and Off-label drug use: None disclosed. Favorable prognostic impact of Konstanze Do¨hner, MD, Department of Internal Medicine III, NPM1 mutations in older patients with cytogenetically normal de novo University Hospital of Ulm, Albert-Einstein-Allee 23, D-89081 acute myeloid leukemia and associated gene- and microRNA- Ulm, Germany; Phone: 49-731-500-45001; Fax: 49-731-500- expression signatures: a Cancer and Leukemia Group B study.

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About 536 million people aged cept of STI refers to the way of transmission 0.25mcg rocaltrol overnight delivery, and 15–49 years were estimated to be living with herpes the concept RTI to the site where the infection 8 simplex virus type 2 worldwide in 2003 (Tables 1 develops discount rocaltrol 0.25 mcg visa. The following chapter includes selected curable STIs and RTIs based on a synthesis of what is generally discussed in textbooks of gynecology and Table 1 Common curable STIs (2005 WHO estimation) obstetrics and World Health Organization (WHO) publications on STIs as well as treatment guide- Million cases lines. Treatment advice is based on WHO treat- per year ment guidelines2,3 and Cochrane reviews4,5, and is Gonorrhea (Neisseria gonorrhoeae) 88 restricted to drugs listed in the Interagency List of Chlamydia infection (Chlamydia trachomatis) 101 Essential Medicines for Reproductive Health6. Syphilis infection (Treponema pallidum) 11 The STIs discussed in this chapter include bacte- Trichomoniasis (Trichomonas vaginalis) 204 rial vaginosis, trichomoniasis, candidiasis, chlamy- Chancroid (Haemophilus ducreyi) 6 dia, gonorrhea, pelvic inflammatory disease (PID), 183 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS Table 2 Common viral infections of interest in who have had PID are six to ten times more likely gynecology and obstetrics to have an ectopic (tubal) pregnancy than those who have not had one. Up to 50% of children cancer every year born to mothers with untreated gonorrhea and 30% of children born to mothers with untreated HPV, human papillomavirus chlamydial infection will develop a serious eye in- fection or conjunctivitis (ophthalmia neonatorum). Untreated STIs, excluding HIV, are estimated to account for 17% of the economic loss due to MANAGEMENT AND TREATMENT disease. Most importantly, for both men and OF SYMPTOMATIC SEXUALLY women, STIs are associated with an increased risk TRANSMITTED INFECTIONS AND of both acquisition and transmission of HIV. The REPRODUCTIVE TRACT INFECTIONS risk of HIV transmission is about two to five times higher in people with an STI, highest in people Sexually transmitted infection syndromes with an ulcerative STI9,10 (level 1 evidence). Re- and the syndromic approach to patient cent evidence suggests that genital herpes (herpes management simplex 2) may be responsible for fuelling a large 11 Although many different pathogens cause STIs or part of HIV infection (level 1 evidence). RTIs, many have a similar or overlapping clinical STIs are more frequent in young women than appearance, known as signs (what the individual or men and more frequent in low-income countries the healthcare provider sees on examination) and where diagnostics and treatment are limited. Signs and symptoms can help health pro- in low-income countries are demographic factors viders make a diagnosis. For example, profuse, (more young people), urbanization, migrant labor, purulent, malodorous vaginal discharge is seen in prostitution, concurrent partnerships, lack of access trichomoniasis. But vaginal discharge is also seen in to quality care for STIs, and for prevention efforts, 12 infections other than STIs, such as bacterial vagino- including screening programs. Often more than Another important factor is that a number of one etiological cause/microbe is involved in the in- STIs are asymptomatic which hampers control fection. Thus the signs and symptoms are often not significant proportion of men with gonococcal specific enough to make an etiological diagnosis. But, tests for STIs are mostly not available at first-line health facilities and often not at district Common complications of sexually hospital level in low-resource settings. Some transmitted infections laboratory investigations for diagnosing STIs are Besides the higher risk of HIV infection, STIs cause expensive or demand advanced techniques. Particularly, untreated is why WHO has recommended a syndromic chlamydial infection is estimated to be the cause of approach to diagnosis and management of STIs in at least a third of female infertility. Also, women low- and middle-income countries since the 1990s 184 Sexually Transmitted Infections and Reproductive Tract Infections and it has been the approach of choice since then in charts are promoted to assist health workers to most settings. The approach is based on a group of decide on the best treatment (Figures 1 and 2). There in different languages3 and many countries have is much evidence, that syndromic management is adapted them to the locally observed resistance effective for treating STIs and has an impact on the patterns of STIs. Dramatic declines in STI rates have The advantage of using this signs and symptom- been observed following the introduction of con- based approach is that the management of STIs is trol measures based on the syndromic approach13. Moreover not only specialists but also clinicians • Urethral discharge in men and nurses can treat patients effectively. However, • Genital ulcer syndromic management is not unanimously • Inguinal bulbo supported. Syndromic management of STIs has • Scrotal swelling been reviewed as being generally effective in treat- • Vaginal discharge ing urethral discharge and genital ulcer disease STIs • Lower abdominal pain in women 14 in men (level 1 evidence). The antimicrobial regimens are chosen Another big challenge for the control of STIs is to cover major pathogens responsible for the syn- that infections are often asymptomatic. Thus guide- management is not suitable for treating asympto- lines differ from country to country in accordance matic infections that require a screening approach. Typically, flow- lower-resource countries, except syphilis testing Patient complains of vaginal discharge, vulval itching or burning Take history, examine patient and assess risk1 • Educate and counsel Abnormal discharge No Any other No • Promote and provide condoms present or vulval genital disease? Yes Yes Use flowchart for Treat for Chlamydia trachomatis, Vulval edema/curd- No lower abdominal pain gonococcal infection, bacterial like discharge, erythema, • Educate and counsel vaginosis and Trichomonas vaginalis excoriations present? Source: WHO treatment modules, 2007 185 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS Patient complains of lower abdominal pain Take history, (including gynecological) and examine (abdominal and vaginal) No Any of the following present? Yes Continue treatment until completed • Educate and counsel • Promote and provide condoms • Offer HIV counseling and testing if both facilities are available Figure 2 Syndromic management: lower abdominal pain. Source: WHO treatment modules, 2007 during pregnancy which therefore provides an im- in all countries according to the epidemiological portant opportunity not to be missed (see more pattern of STIs and resistance against antibiotic reg- under Linkages). Furthermore, control efforts need imens, we will not include any specific syndromic to be put on many pillars, where treatment of management treatment advice. We would also like symptomatic diseases is one, but prevention of risky to promote the use of the STI training modules sexual relations, partner notification, screening available from the WHO homepage: http://www. The following sections aim to give an overview The syndromic approach has been particularly about clinical presentation, signs and symptoms and designed for the primary healthcare level.

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Although different estimates vary discount rocaltrol 0.25mcg without prescription, roughly half of all AD patients are in the early or mild disease stage and the other half are in the moderate to 4 severe range of severity discount rocaltrol 0.25mcg visa. The projected prevalence of AD will approximately double over the next 20 years, as a result of the aging of the post-WWII baby-boomer generation. Since the total current economic burden posed by AD, including direct costs (medical, hospital, and nursing home care) and indirect costs (lost productivity of caregivers) is estimated to exceed $85 billion a 5 year, the current and looming economic impact of AD is staggering. The overall cost of managing AD is significantly greater for patients with severe disease than for those with mild to moderate; the reasons are largely greater dependency needs, higher resource utilization, and increased rate of institutionalization. The comprehensive management of AD entails both nonpharmacologic and pharmacologic interventions. Nonpharmacologic interventions primarily address behavioral disturbances (e. Pharmacologic strategies have focused on modulating disease-associated neurotransmitter alterations; strategies can be characterized as symptomatic or neuroprotective. Although a symptomatic and a neuroprotective pharmacologic treatment may have similar outcome characteristics in a clinical trial, the key difference is that a neuroprotective therapy will have a cumulative benefit that persists after the treatment is discontinued. Currently available pharmacologic therapies, including cholinesterase inhibitors (ChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists, are considered symptomatic treatments based on their ability to slow the clinical progression of symptoms across cognitive, behavioral, and functional domains. Among different strategies employed to increase synaptic levels of acetylcholine (ACh), blocking the breakdown of ACh by inhibiting acetylcholinesterase (AChE) has proven most successful to date. Inhibiting the enzyme butyrylcholinesterase (BuChE), which is a minor constituent in normal brains but in the brains of AD patients is increased in association with 7 plaques and tangles, may also improve cholinergic transmission. Centrally active ChEIs, which differ in targeting AChE alone or affecting both AChE and BuChE, were the first class of drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD. Currently available ChEIs include donepezil hydrochloride (donepezil), galantamine hydrochloride (galantamine), rivastigmine tartrate (rivastigmine), and tacrine hydrochloride (tacrine). Among these agents galantamine also acts as an allosteric nicotinic receptor modulator, which has been shown to 8 stimulate the presynaptic release of acetylcholine and other neurotransmitters in laboratory preparations. Because of their more favorable therapeutic profiles, greater convenience, and absence of liver toxicity, the second-generation ChEI agents (i. Neuropharmacologic and pharmacokinetic properties of the currently available ChEIs are summarized in Table 1. More recent evidence implicates the excitatory neurotransmitter glutamate as playing a role in the 9-11 pathophysiology of AD. Currently, the only available drug targeting cognitive symptoms via a putative glutamatergic mechanism is memantine hydrochloride (memantine). Memantine has been widely used in Germany for more than two decades to treat a variety of conditions, including dementia, PD, neurogenic 12, 13 bladder, and neuropathic pain. Memantine has been promoted as a treatment for dementia in Germany since 1989; in 2002 the European Union approved its use in AD. Memantine is a low-affinity noncompetitive NMDA receptor antagonist that blocks pathologic neural toxicity associated with prolonged glutamate release without interfering with the normal physiologic actions of glutamate required 14, 15 for learning and memory functions. Neuropharmacologic and pharmacokinetic properties of memantine are summarized in Table 1. Other more poorly documented pharmacologic approaches include drugs like nicotine, selegiline, vitamin E, ginkgo biloba, piracetam, hormone replacement therapy, anti-inflammatory drugs, statins, and folic 14, 16 acid; these will not be considered in this review. Current drug treatments for Alzheimer’s disease Tacrine Donepezil Rivastigmine Galantamine Memantine Agent (Cognex ) (Aricept ) (Exelon ) (Razadyne (Namenda™) Razadyne ER ) Manufacturer/ West-Ward Eisai Novartis Janssen Merz Distributor Horizon Pfizer Shire Forest Mechanism(s) AChEI, BuChEI AChEI AChEI, BuChEI AChEI, NRM NMDA antagonist d Dose Forms 10, 20, 30, 40 5, 10 1. Scope and key questions The purpose of this review is to help policy makers and clinicians make informed choices about the use of the four ChEIs and memantine in the treatment of AD. We compare the efficacy, effectiveness, and safety (adverse events) of donepezil, galantamine, rivastigmine, tacrine, and memantine in patients with mild to severe AD. Although we will emphasize comparative head-to-head studies, the few published ones do not allow for a comprehensive evaluation. Accordingly, we will also include supplementary data from individual placebo-controlled trials and observational studies. The participating organizations of the Drug Effectiveness Review Project (DERP) are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to their constituencies. The Oregon Evidence-based Practice Center initially prepared preliminary key questions identifying the populations, interventions, and outcomes of interest, and we based the eligibility criteria for studies on these preliminary questions. Representatives of organizations participating in the DERP, in conjunction with experts in the fields of health policy, neurology, pharmacotherapy, and research methods reviewed, revised, and approved the questions and outcome measures. The participating organizations approved the following key questions: 1. How do donepezil, galantamine, rivastigmine, tacrine, and memantine or combinations of these drugs (i. How do donepezil, galantamine, rivastigmine, tacrine, and memantine (or combinations of these drugs) compare in their time to effect and in the time required to assess the clinical response? What are the comparative incidence and severity of complications of donepezil, galantamine, rivastigmine, tacrine, and memantine (or combinations of these drugs)?

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