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The usual diagnostic approach to a patient with a suspicious thyroid mass involves 99mTc pertechnetate thyroid scintigraphy and thyroid ultrasound imaging. Where thyroid cancer is confirmed, a near total thyroidectomy is performed but the surgical protocol may depend upon the size of the nodule, and estimated extent of disease. Five or six different laboratories in Paraguay assay anti-thyroglobulin antibody levels and also use appropriate dilutions. There is usually good patient compliance with the first follow-up visit at six months, but the loss to follow-up is high after this time. Furthermore, all imported 131I and other radiopharmaceuticals have to go through the standard administrative process at 131 231 customs, also adding to the delay in obtaining these products at the airport. In Paraguay there is no government support or private organizations offering support for nuclear medicine. With only three practicing nuclear medicine physicians, limited equipment and no government support, the speciality of nuclear medicine in Paraguay is unlikely to keep pace with other countries. This has been based largely upon standards and regulations set as benchmarks from North America and Europe, where resources are most available for research and data collection. Even countries with very few resources have a basic infrastructure in place that allows physicians to follow the recommended management protocols. The profound lack of resources in some countries however, prevents optimal basic diagnosis and limited follow-up (Tables 17. This may prohibit therapy in some cases, and result in increased costs of transport and overnight accommodation for patients who cannot afford such expense. Poverty, poor transport infrastructure and geographic isolation all contribute to inadequate long term management of patients with thyroid cancer in many developing countries. Continuing education of physicians is required in order to instigate appropriate management algorithms. In turn, the physicians need to promote education of the general public and dispel misinformation, so that patients will seek appropriate medical help as early as possible. In many countries cultural factors may also inhibit appropriate management of thyroid cancer. Patients may seek traditional family therapies as alternatives to modern medicine, and due to lack of information, may fear modern medical equipment and techniques. Even with the introduction of new equipment and staff, unless data is collected that accurately reflects the impact, or otherwise, of any change, the true benefit of change cannot be assessed. However, this review indicates that there is much potential for improvement, and also that an inertia of knowledge growth has developed that should provide us with optimism for the future. The long term follow-up studies of external radiation-exposed victims of Hiroshima and Nagasaki have indicated the elevated risk of thyroid cancer during the lifespan of exposed individuals. The genes subject to mutations in thyroid carcinogenesis can be classified as oncogenes or anti-oncogenes (tumour suppressor genes) based on their mode of action. Some genetic changes leading to thyroid cancer are inherited through the germline, but most are acquired or somatic in nature. Especially discussed is the molecular mechanism of radiation-induced thyroid carcinogenesis. In general, these genes, when turned on, promote cell growth, division and depress differentiation. The escape mechanism from cell apoptosis is also critical for abnormal cell proliferation. Another important oncogene is frequently and specifically expressed in papillary thyroid cancers. Anti-oncogenes Compared to oncogene activation, second mechanism of thyroid carcinogenesis arises from inactivating mutations in genes that normally serve to limit cell proliferation. Thus, evidence for characteristic chromosomal abnormalities within tumour cells may lead to recognition of a tumour suppressor gene. The involvement of cell cycle regulators remains to be further clarified at the standpoint of tumour suppressor gene during thyroid oncogenesis. Genetic background of radiation-induced tumourigenesis the genetic background of an individual can influence the susceptibility to carcinogenesis. Germ line mutations in antioncogenes such as p53 or pRb may result in an increased prevalence of both spontaneous and induced tumours.
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Laboratory quality is ensured by the Clinical Laboratory Improvement Amendments, accreditation by the College of American Pathologists and other professional societies, and individual state requirements. However, this process is much less burdensome and orders of magnitude less expensive for in vitro diagnostic kits than for drugs. Rather, enforcement of gene patents in the diagnostic realm results in the elimination of already existing services and dissuades laboratories from adding new ones. Moreover, loss of academic providers will adversely affect training and related clinical research. Greater interest in companion diagnostic development by the pharmaceutical industry may alter the preceding dynamics. Control of companion diagnostics could allow drug manufacturers to ensure assay standardization, enforce specific quality requirements, and provide additional sources of revenue. Companion diagnostics could serve as vehicles by which companies preserve market share for linked drugs, assuming they avoid patent misuse or antitrust violations. Under this model, gene-related patents may create incentives for marker discovery and in vitro diagnostic commercialization. However, such patents could prove a double-edged sword by creating holdout problems for drug vendors who do not own the underlying molecular pathologic relationships. Several cases presently making their way through the courts may clarify and add reason to the law in this area. Patents on human gene sequences have likely helped stimulate the introduction of novel biologics and pharmaceutical agents. Conversely, patents on human gene sequences and genotype-phenotype correlations appear to reduce the availability of and patient access to already existing diagnostic services, while increasing costs and decreasing innovation in the development of diagnostic methods. The intellectual property rules by which patents on human genes and genotype-phenotype associations are governed will have a profound impact on the advancement of personalized cancer care. Several key legal cases now before the courts may add clarity and guidance to the law governing this area. The patent claims at issue include "administering a drug," "determining the level" of a metabolite of the drug, and correlating this level with therapeutic efficacy or side effects. The district court found as a matter of law that the patent, which essentially claims the reference range for the drugs, covered an unpatentable natural phenomenon. Of note, during oral arguments, the attorney for Prometheus Labs acknowledged that it had patented "a fact" they identified, and that physicians can infringe the patent merely by thinking about the biologic relationship between metabolite levels and patient response. Many if not most patented genes were initially mapped to a chromosomal region before discovery. Moreover, many genes are involved in sequential biochemical pathways in which disease-related changes were known before specific genetic variations were identified. Therefore, for many of these discoveries, it was arguably obvious to look for variants in the potentially responsible genes among the finite number of available solutions. In addition to arguing that the patents claim unpatentable natural products and natural phenomena, the plaintiffs asserted that they violate Article I, section 8, clause 8 and the First Amendment to the U. These patent claims, the court ruled, were directed toward unpatentable subject matter. Conclusion Genes as chemicals have an important role to play in therapeutic development. Therefore, a prudent course for the courts when addressing gene-related patents is to strike a balance, upholding their validity when the patents protect drug development, while denying their enforceability when the patents create the potential for genetic testing monopolies. Revised Draft Report on Gene Patents and Licensing Practices and Their Impact on Patient Access to Genetic Tests (2010). LabCorp v Metabolite Laboratories: the Supreme Court listens, but declines to speak. Effects of patents and licenses on the provision of clinical genetic testing services. Despite clinical guidelines that recommend physicians counsel high-risk women about the use of chemoprevention and the estimated 2. However, many physicians remain unaware of these resources to determine patient eligibility for chemoprevention and lack the time to provide informed counseling to their patients. Despite these challenges, there are substantial opportunities to increase the utilization of chemoprevention. There was a nonstatistically significant higher risk of noninvasive breast cancer from raloxifene, which diminished at longer follow-up.
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The daVinci technique allows for patients to return to work more quickly than standard laparoscopy or open cases due to decreased pain. They also use less post operative pain medication, have fewer infections, less blood loss, and fewer postoperative complications. As a surgeon, my back pain is drastically improved after switching to the daVinci robotic technique. This benefits patients, because they will have more experienced surgeons able to operate longer. Our group made a conscious decision to enter robotic surgery and now use it for selected thoracic and esophageal procedures. The robot allows surgeons with average or limited minimally invasive laparoscopic skills to do more complex cases that they would otherwise perform open. Most of the studies showing lack of benefit to the robot compare results with surgeons highly skilled in both laparoscopic and robotic surgery and would therefore not show this dynamic. The robot is being over-utilized by surgeons wanting to improve their skills or to market their practice. If restrictions are necessary for financial reasons, it would be much preferable to create boundaries either by institution or practice rather than prohibiting it altogether. Lost time from work was far less in my robotic experience (7 days total) than the typical 6-10 weeks that we see in traditional open procedures. In short, if my experience is any indicator of the reduced hospital resources consumed and the vastly shortened recovery times that can be realized through the use of Robotic assisted surgery, then this is a technology that should encouraged for all appropriate procedures. After a few cases, the answer to my question became obvious-it was a resonding yes! I have done fibroids to 27 weeks size with the robot, and taken out as many as 36 fibroids at one time. I have been performing this operation for 22 years and am an expert at Open Radical Retropubic Prostatectomy with Bilateral pelvic Lymph Node Dissection. The open procedure is better in terms of cost, operative time, blood loss, and incontinence rates. The dichotomy between new technology and evidence based medicine is that the early lack of data to demonstrate value inhibits the training, use and deployment of technologies that will likely benefit a significant number of patients. Robotic surgery allows surgeons to perform minimally invasive surgery with better visualization and precision than in laparoscopic procedures. Unfortunately the cost and training in robotic surgery is expensive but the benefits to the patients will be realized as it has been in laparoscopic surgery. Prior experience in laparoscopic surgery is extremely valuable in reducing the robotic learning curve. Robotic programs should critically analyze their data to bolster the evidence to support this valuable technology. My leap to training and using the robot for gyn surgery has helped so many of my patients. Prior to using the robot for gyn surgery, I was attempting a laparoscopic approach in complex surgical situations. While laparoscopy is still a valuable tool, I found that my dependence on my assistant surgeon during the case and my limited ability to articulate the laparoscopic instruments would sometimes lead to requiring an open laparotomy incision (large incision) in order to finish the case. This was most unfortunate for my patients, especially the morbidly obese patients with complex medical problems. Ever since I started using the robot, I have only used a laparotomy incision (large incision) on one patient in gyn surgery. The robot has given me the tools I need to perform minimally invasive surgery on some of the most complicated and challenging patients. By using the robot, I have been able to minimize their stays in the hospital and shorten recovery times. My understanding is that Medicaid does not pay any extra fees for robotic surgery on patients. The robot is considered a laparoscopic tool and therefore all cases are reimbursed as though they were straight laparoscopic. If this is the case, then I confused as to why the state would be concerned as to whether Robotic surgery is covered in their plans or not. And, patients benefit from robotics by avoiding large incisions that often lead to secondary complications such as infections, seromas, separations and longer healing times.
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Body mass index and risk of renal cell cancer: A dose-response metaanalysis of published cohort studies. Body burdens of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls and their relations to estrogen metabolism in pregnant women. Unraveling the interactions between environmental factors and genetic polymorphisms in non-Hodgkin lymphoma risk. Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinognesis in rats. Military service in Vietnam and the risk of death from trauma and selected cancers. Cancer incidence in the rural community of Tecumseh, Michigan: A pattern of increased lymphopoietic neoplasms. Carcinogenicity of dimethylarsinic acid in male F344 rats and genetic alterations in incuded urinary bladder tumors. Pre- and postconception pesticide exposure and the risk of birth defects in an Ontario farm population. Mechanisms of intestinal inflammation and development of associated cancers: Lessons learned from mouse models. Environmental toxicants and the developing immune system: A missing link in the global battle against infectious disease? Potential involvement of placental AhR in unexplained recurrent spontaneous abortion. Biokinetics and subchronic toxic effects of oral arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg. Aryl hydrocarbon receptor activation attenuates Per1 gene induction and influences circadian clock resetting. Role of the critical period in sex and brain differentiation: Learning from dioxin-induced disorders in next generations. A cross-sectional analysis of dioxins and health effects in municipal and private waste incinerator workers in Japan. Exposure to dimethylarsinic acid, a main metabolite of inorganic arsenics, strongly promotes tumorigenesis initiated by 4-nitroquinoline 1-oxide in the lungs of mice. The organochlorine pesticides residues in the invasive ductal breast cancer patients. Agent Orange exposure and cancer incidence in Korean Vietnam veterans: A prospective cohort study. Agent Orange exposure and prevalence of selfreported diseases in Korean Vietnam veterans. Agent Orange exposure and disease prevalence in Korean Vietnam veterans: the Korean Veterans Health Study. Agent Orange exposure and risk of death in Korean Vietnam veterans: Korean Veterans Health Study. Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion. Reproductive lesions in female Harlan Sprague-Dawley rats following two-year oral treatment with dioxin and dioxin-like compounds. Thyroid follicular lesions induced by oral treatment for 2 years with 2,3,7, 8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds in female Harlan Sprague-Dawley rats. Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells. A mortality study of workers employed at the Monsanto company plant in Nitro, West Virginia. Environmental risk factors for women with polycystic ovary syndrome in China: A population-based case-control study. Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor. Differences of urinary arsenic metabolites and methylation capacity between individuals with and without skin lesions in Inner Mongolia, Northern China. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Insights into the substrate specificity, inhibition, regulation, and polymorphism and the clinical impact of human cytochrome P450 1A2. Increased expression of aryl hydrocarbon receptor and interleukin 22 in patients with allergic asthma.
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Environmental and occupational exposure of metals and their role in male reproductive functions. Association of asthma with use of pesticides: Results of a cross-sectional survey of farmers. The role of the aryl hydrocarbon receptor in normal and malignant B cell development. Modulation of natural killer cell antitumor activity by the aryl hydrocarbon receptor. Higher urinary heavy metal, phthalate, and arsenic but not parabens concentrations in people with high blood pressure, U. Incidence and prevalence of multiple allergic disorders recorded in a national primary care database. Persistent organic pollutants and abnormal geometry of the left ventricle in the elderly. Soft tissue sarcoma and exposure to phenoxyherbicides and chlorophenols in New Zealand. Post-traumatic stress disorder among American Legionnaires in relation to combat experience in Vietnam: Associated and contributing factors. Effect of developmental dioxin exposure on methylation and expression of specific imprinted genes in mice. Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation. Ontogeny of swimming behavior and brain catecholamine turnover in rats prenatally exposed to a mixture of 2,4-dichlorophenoxyacetic and 2,4, 5-trichlorophenoxyacetic acids. The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. Pesticide use and incident diabetes among wives of farmers in the Agricultural Health Study. The effect of in utero exposure to dioxins and polychlorinated biphenyls on reproductive development in eight yearold children. Thyroid and growth hormone concentrations in 8-year-old children exposed in utero to dioxins and polychlorinated biphenyls. The relationship between Agent Orange and prostate specific antigen: A comparison of a hotspot and a non-sprayed area in Vietnam. Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men. Effect-based hazard identification of house dust by in vitro assays detecting dioxin-like compounds, thyroid and reproductive toxicants. Distributions and chemical forms of arsenic after intravenous administration of dimethylarsinic and monomethylarsonic acids to rats. Dioxins and cytogenetic status of villagers after 40 years of Agent Orange application in Vietnam. Human papilomavirus in head and neck cancer: Molecular biology and clinicopathological correlations. Sex ratio of the offspring of New Zealand phenoxy herbicide producers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Effects of perinatal dioxin exposure on development of children during the first 3 years of life. The enhancing effect of the antioxidant n-acetylcysteine on urinary bladder injury induced by dimethylarsinic acid. Dioxin silences gonadotropin expression in perinatal pups by inducing histone deacetylases: A new insight into the mechanism for the imprinting of sexual immaturity by dioxin. Risk of adverse reproductive outcomes associated with proximity to municipal solid waste incinerators with high dioxin emission levels in Japan. Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions. Dioxin risk assessment: Mechanisms of action and possible toxicity in human health. Neurodevelopmental retardation, as assessed clinically and with magnetoencephalography and electroencephalography, associated with perinatal dioxin exposure. Mortality and morbidity among Army Chemical Corps Vietnam veterans: A preliminary report.
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The abundance of invertebrates in forests with high acid deposition is reported to be up to eight times less than in forests not exposed to acid deposition (Bredin 2009). Adult migratory songbirds in general experience the vast majority of annual mortality during seasonal migration (Sillet and Holmes 2002). Species formerly restricted to lower elevations by cold temperatures may move upslope in response to warming temperatures and associated changes in prey base or other resources (Lambert et al. Of these visitors to the White Mountain National Forest, about 31,400 visited the backcountry (King et al. Studies indicate that some birds avoid recreational trails and might even experience higher nest predation in more heavily used areas (King et al. Ski area development should maintain forested "islands" as large as possible between ski trails, minimize the width of trails, and maximize habitat connectivity in developed areas to increase suitability for nesting and foraging. Timber managers should also seek to maintain patches of intact (un-thinned) forest (BirdStudies Canada 2009). Without prompt and decisive political action, regional efforts to protect habitat will eventually be eclipsed by ecosystem-scale shifts in forest composition, and climate-associated changes in the dynamics of weather, prey, predators, disease, and other factors. We believe that all current and historic nesting sites on the mountaintops of upstate New York, Vermont, New Hampshire and Maine meet the criteria for designation as critical habitat and must therefore be designated as such. The widespread threats to this species have been acknowledged by several federal, state, and private agencies, but no formal regulatory protections have yet been afforded to this ecologically specialized and sensitive songbird. Biologist Zoe Sheldon of the Center for Biological Diversity did much to help complete it. Predictions of future climate change in the Caribbean region using global general circulation models. A rapid upward shift of a forest ecotone during 40 years of warming in the Green Mountains of Vermont. Proceedings of the National Academy of Sciences of the United States of America 104:18866-18870. The latitude-elevation relationship for spruce-fir forest and treeline along the Appalachian Mountain chain. Changes in Geographical Range Resulting from Greenhouse Warming: Effects on Biodiversity in Forests. Contribution of Working Group I to the Fourth Assessment Report of the Intergovernmental Panel on Climate change. Mercury contamination in forest and freshwater ecosystems in the northeastern United States. Acid Rain Revisited: Advances in Scientific Understanding Since the Passage of the 1970 and 1990 Clean Air Act Amendments. Nitrogen pollution in the northeastern United States: Sources, effects, and management options. Mercury Connections: the extent and effects of mercury pollution in northeastern North America. Climate Change: Trends in Greenhouse Gas Emissions and Emissions Intensity in the United States and Other HighEmitting Nations. Adverse effects of acid rain on the distribution of Wood Thrush (Hylocichla mustelina) in North America. Expert report submitted to the United States District Court, Eastern District of California in regard to Case No. Witherspoon: the Case for Action by the State of California to Mitigate Climate Change. Proceedings of the National Academy of Sciences of the United States of America 103:14288-14293. Mountain Birdwatch 2006: Final Report to the United States Fish and Wildlife Service. Contribution of Working Group I to the Third Assessment Report of the Intergovernmental Panel on Climate Change (Houghton, J.
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In addition, because of vasodilation in the contracting muscles, peripheral resistance and, consequently, afterload are decreased. Note that stroke volume levels off, then falls somewhat (as a result of the shortening of diastole) when the heart rate rises to high values. One of the differences between untrained individuals and trained athletes is that the athletes have lower heart rates, greater end-systolic ventricular volumes, and greater stroke volumes at rest. Therefore, they can potentially achieve a given increase in cardiac output by further increases in stroke volume without increasing their heart rate to as great a degree as an untrained individual. O2 consumption by the heart is determined primarily by the intramyocardial tension, the contractile state of the myocardium, and the heart rate. The work is the product of stroke volume and mean arterial pressure in the pulmonary artery or the aorta (for the right and left ventricle, respectively). Because aortic pressure is 7 times greater than pulmonary artery pressure, the stroke work of the left ventricle is approximately 7 times the stroke work of the right. However, for reasons that are incompletely understood, pressure work produces a greater increase in O2 consumption than volume work. In other words, an increase in afterload causes a greater increase in cardiac O2 consumption than does an increase in preload. This is why angina pectoris due to deficient delivery of O2 to the myocardium is more common in aortic stenosis than in aortic insufficiency. In aortic stenosis, intraventricular pressure must be increased to force blood through the stenotic valve, whereas in aortic insufficiency, regurgitation of blood produces an increase in stroke volume with little change in aortic impedance. It is worth noting that the increase in O2 consumption produced by increased stroke volume when the myocardial fibers are stretched is an example of the operation of the law of Laplace. This law, which is discussed in detail in Chapter 32, states that the tension developed in the wall of a hollow viscus is proportionate to the radius of the viscus, and the radius of a dilated heart is increased. O2 consumption per unit time increases when the heart rate is increased by sympathetic stimulation because of the increased number of beats and the increased velocity and strength of each contraction. However, this is somewhat offset by the decrease in end-systolic volume and hence in the radius of the heart. The dicrotic notch on the aortic pressure curve is caused by A) closure of the mitral valve. The work performed by the left ventricle is substantially greater than that performed by the right ventricle, because in the left ventricle A) the contraction is slower. D) explains the increase in cardiac output that occurs when venous return is increased. E) explains the increase in cardiac output when the sympathetic nerves supplying the heart are stimulated. The proportion of blood leaving the ventricles in each cardiac cycle is called the ejection fraction and is a sensitive indicator of cardiac health. Initially, this is manifested only during exercise, but eventually the heart will not be able to supply sufficient blood flow even at rest. The second heart sound is caused by A) closure of the aortic and pulmonary valves. The fourth heart sound is caused by A) closure of the aortic and pulmonary valves. Understand the molecular basis of blood groups and the reasons for transfusion reactions. Delineate the process of hemostasis that restricts blood loss when vessels are damaged, and the adverse consequences of intravascular thrombosis. Identify the types of blood and lymphatic vessels that make up the circulatory system and the regulation and function of their primary constituent cell types. Describe how physical principles dictate the flow of blood and lymph around the body. Understand the basis of methods used to measure blood flow and blood pressure in various vascular segments. Understand the basis of disease states where components of the blood and vasculature are abnormal, dysregulated, or both. The blood, the carrier of these substances, is pumped through a closed system of blood vessels by the heart.
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Prognostic factors in patients with well-differentiated thyroid cancer presenting with pulmonary metastasis. Although thyroid cancers have historically been more in the purview of endocrinologists than of medical oncologists, recent therapeutic innovations have made it increasingly important that medical oncologists develop expertise in the management of thyroid cancers, especially when advanced. The following sections review recent progress in developing more effective systemic therapies for advanced thyroid cancers (Table 1), discussing each of the three major histotypes in separate sections, and providing general rationale for the application of available systemic therapies. In decisions related to systemic therapy it is, therefore, important to carefully weigh the anticipated risks and benefits of a candidate treatment compared with the risks imposed by the disease itself. Alternatives for focal palliation of areas of threatening disease (especially in the neck and in bone) should first be prominently considered before initiation of systemic therapies. Moreover, the risk imposed by the disease versus by the systemic approaches under consideration should be carefully weighed. Although considerable recent progress has been made in better understanding candidate therapeutic targets and approaches to treating advanced thyroid cancers, additional and more effective systemic therapies for these cancers remain sorely needed. As a result, there should be prominent consideration of focal palliation of locally threatening disease (especially in the neck and in bone) before initiation of systemic therapies. Similarly, the application of cytotoxic chemotherapy is often associated with nausea, cytopenias, and other adverse effects that have potential to adversely affect patient quality of life and impose risks to patient welfare. In applying this approach, several groups have observed unexpectedly favorable outcomes and survival,21,22 suggesting that it may be fruitful in patients with good performance status seeking an aggressive approach to their initial therapy. This situation has recently begun to change with the elaboration of an increasing amount of information related to the molecular pathways contributing to thyroid cancer pathogenesis, thereby resulting in the identification of an ever-increasing array of candidate therapeutic molecular targets that has already begun to lead to therapeutic advances in thyroid cancers. Nevertheless, despite considerable recent progress, further basic advances and therapeutic progress related to thyroid cancers are still very much needed, especially for patients with rapidly progressive metastatic disease. Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single-institution experience using aggressive multimodal therapy. High efficacy of concomitant treatment of undifferentiated (anaplastic) thyroid cancer with radiation and docetaxel. These tumors have historically been treated in a manner similar to that used for higher-grade tumors but, more recently, it has become evident that with a plan of active surveillance that reserves treatment for only those patients whose tumors show evidence of progression, very high disease-specific survival can be achieved. Unfortunately, the frequency of recommendation of an active surveillance strat- egy in the United States is low. An alternative strategy to improve prostate cancer detection is through selected biopsy of those men who are at greater risk of harboring high-grade, potentially lethal cancer. This strategy is currently possible through the use of risk assessment tools such as the Prostate Cancer Prevention Trial Risk Calculator. At its most basic level, the opportunity for overdiagnosis of prostate cancer (overdiagnosis can be defined as detection of cancers that will ultimately not harm the host) must be understood to be related to the background rate of the disease. The best insight into this potential opportunity for diagnosis of prostate cancer comes from autopsy studies of men who died as a result of other causes. Careful sectioning of prostates in these men gives us an idea as to the lower bound estimate for the risk of the disease. Indeed, to make a diagnosis of prostate cancer, which is generally asymptomatic until metastases develop, there are three prerequisites: 1) the physician must suspect cancer, 2) the patient must accept a prostate biopsy, and 3) the biopsy needle must strike the tumor. How Is the Prostate Cancer of 2012 Different from the Prostate Cancer of Prior Decades? In one series we conducted prospectively in the early 1980s, in 2,005 men undergoing biopsy, only 65 abnormal examinations were identified. Additionally, it was not uncommon for a physician to obtain as few as two biopsy cores from the prostate in determining whether cancer was present. Certainly, because prostate cancer is multifocal and oftentimes occupies a small fraction of the gland, this poor sampling of the prostate missed many small tumors.
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These sharp boundaries between wakefulness and sleep are a key feature of normal physiology, as it would be maladaptive for animals to walk around half-asleep or to spend long portions of their normal sleep cycle half-awake. This mutually inhibitory relationship ensures that transitions between wake and sleep are rapid and complete. Both conditions are due, ultimately, to lack of activity by the ascending arousal system. However, in sleep, the lack of activity is due to an intrinsically regulated inhibition of the arousal system, whereas in coma the impairment of the arousal system is due either to damage to the arousal system or to diffuse dysfunction of its diencephalic or forebrain targets. Because sleep is a regulated state, it has several characteristics that distinguish it from coma. Patients who are obtunded may be aroused briefly, but they require continuous stimulation to maintain a wakeful state, and comatose patients may not be arousable at all. In addition, sleeping subjects undergo a variety of postural adjustments, including yawning, stretching, and turning, which are not seen in patients with pathologic impairment of level of consciousness. The Cerebral Hemispheres and Conscious Behavior the cerebral cortex acts like a massively parallel processor that breaks down the components of sensory experience into a wide array of abstractions that are analyzed independently and in parallel during normal conscious experience. The cerebral neocortex of mammals, from rodents to humans, consists of a sheet of neurons divided into six layers. Recordings of neurons in each successive layer of a column of visual cortex, for example, all respond to bars of light in a particular orientation in a particular part of the visual field. A summary drawing of the laminar organization of the neurons and inputs to the cerebral cortex. The neuronal layers of the cerebral cortex are shown at the left, as seen in a Nissl stain, and in the middle of the drawing as seen in Golgi stains. The organization of the cortical column does not vary much from mammals with the most simple cortex, such as rodents, to primates with much larger and more complex cortical development. The depth or width of a column, for example, is only marginally larger in a primate brain than in a rat brain. The hugely enlarged sheet of cortical columns in a human brain provides the massively parallel processing power needed to perform a sonata on the piano, solve a differential equation, or send a rocket to another planet. An important principle of cortical organization is that neurons in different areas of the cerebral cortex specialize in certain types of operations. In a young brain, before school age, it is possible for cortical functions to reorga- nize themselves to an astonishing degree if one area of cortex is damaged. However, the organization of cortical information processing goes through a series of critical stages during development, in which the maturing cortex gives up a degree of plasticity but demonstrates improved efficiency of processing. Hence, the individual with a large right parietal infarct not only loses the ability to appreciate stimuli from the left side of space, but also loses the concept that there is a left side of space. Such a patient continues to speak meaningless babble and is surprised that others no longer understand his speech because the very concept that language symbols are embedded in speech eludes him. This concept of fractional loss of consciousness is critical because it explains confusional states caused by focal cortical lesions. It is also a common observation by clinicians that, if the cerebral cortex is damaged in multiple locations by a multifocal disorder, it can eventually cease to function as a whole, producing a state of such severe cognitive impairment as to give the appearance of a global loss of consciousness. During a Wada test, a patient receives an injection of a short-acting barbiturate into the carotid artery to anesthetize one hemisphere so that its role in language can be assessed prior to cortical surgery. When the left hemisphere is acutely anesthetized, the patient gives the appearance of confusion and is typically placid but difficult to test due to the absence of language skills. When the patient recovers, he or she typically is amnestic for the event, as much of memory is encoded verbally. Following a right hemisphere injection, the patient also typically appears to be confused and is unable to orient to his or her surroundings, but can answer simple questions and perform simple commands. The experience also may not be remembered clearly, perhaps because of the sudden inability to encode visuospatial memory. However, the patient does not appear to be unconscious when either hemisphere is acutely anesthetized. An important principle of examining patients with impaired consciousness is that the condition is not caused by a lesion whose acute effects are confined to a single hemisphere. A very large space-occupying lesion may simultaneously damage both hemispheres or may compress the diencephalon, causing impairment of consciousness, but an acute infarct of one hemisphere does not. Hence, loss of consciousness is not a typical feature of unilateral carotid disease unless both hemispheres are supplied by a single carotid artery or the patient has had a subsequent seizure. The concept of the cerebral cortex as a massively parallel processor introduces the question of how all of these parallel streams of information are eventually integrated into a single consciousness, a conundrum that has been called the binding problem.
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Molecular approaches to epidemiology use a priori hypotheses and biomarkers, rather than simply seeking associations between an exposure and disease (. First, carcinogenesis is a multistage process, and behind each stage are genetic events and complex pathways that may be responsible for these events. Thus, characterizing a specific risk factor against a background of many risk factors is difficult for scientists and can limit statistical power. Schematic model depicting the range (from exposure to effect) and types of biomarkers that might be used for cancer risk assessments. The carcinogenic process is driven by genetic events (mutations or epigenetic changes), and in most people they are triggered by environmental exposures modified by host susceptibility. Gatekeeper genes are involved in normal cellular function, such as those that are involved in cell-cycle control or apoptosis. Also, given that cancers are caused by multiple exposures causing damage in different genes, now the carcinogenic process is being considered as gene N-environmentN interactions. This new paradigm will lead to different perspectives of cancer genetics and cancer risk factors, wherein some genetic effects will be modeled differently (see. A variety of assays are available to identify carcinogen-macromolecular adducts in human tissues. Each has its usefulness and limitations, and all are challenged by sensitivity or specificity (or both). The detection of gross chromosomal changes in normal-appearing cells is technically difficult. Presumed surrogate measures of chromosomal damage include the estimate of sister chromatid exchanges or baseline gross chromosomal changes. The latter has been associated with increased cancer risk, but these studies have significant limitations. The greatest source of exposure in the United States is from processed meats and (until recently) beer. Endogenous formation occurs in the stomach from the reaction of nitrosatable amines and nitrate, used as a preservative, which is converted to nitrites by bacteria. Host capacity to form N-nitrosamines is associated with risk of stomach 89 and esophageal cancer. Industrial pollution, fossil fuels, and tobacco smoke account for the major environmental sources, although diet is considered the major source. Some of the largest carcinogenic occupational exposures occur in the dye industry. Levels are higher in smokers than in nonsmokers, and different types of tobacco can lead to higher adduct levels. They are formed from the cooking of meat, poultry, and fish as a result of the condensation of amino acids and creatine during pyrolysis. Aflatoxin remains one of the best examples of the range and use of biomarkers for cancer risk (see. The primary adduct formed from aflatoxin exposure is to the N7 position of guanine. Table 11-6 lists several investigated genetic polymorphisms and their association with cancer risk. Selected Examples of Inherited Susceptibilities for Cancer Lung cancer has been studied most extensively for gene-environment interactions. Phenotypically and genetically, this polymorphism has been related to lung cancer risk. One study has implicated cytochrome 17, 123 whereas others have provided conflicting evidence for catechol-methyltransferase that detoxifies estradiol. An increased mutagen-related aberration rate has been observed in persons with primary and secondary upper aerodigestive tract cancers, 140 multiple primary cancers, 141 and lung cancer. In eukaryotic studies, for example, examining the mutational spectra in endogenous genes 144 or exogenous genes transfected into cell systems 145,146 have identified different phenotypes, depending on the exposures. These assays, however, may underestimate the induced mutational frequency due to deletions, chromosomal nondysjunction, and frameshift mutations that cause loss of other genes essential for cell survival and result in cytotoxicity or apoptosis.