Katarzyna Jadwiga Macura, M.D., Ph.D.

• Assistant Director ICTR Imaging Translational Program
• Professor of Radiology and Radiological Science

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0015445/katarzyna-macura

Other risk factors for colorectal carcinoma are likely to relate to chronic inflammation and the disordered structure of the mucosal crypts on the surface of the bowel medicine quinidine zerit 40mg. Patients with inflammatory bowel disease have an increased risk of developing colorectal cancer symptoms 0f pregnancy order zerit 40mg mastercard, and this risk is proportional in magnitude to the duration of the diagnosis symptoms narcolepsy order zerit in united states online. Lifestyle and diet are environmental factors that are thought to explain some of the geographic differences in the incidence of bowel cancer symptoms questions purchase zerit online now. Fewer than 2 cases per 100 000 people are seen in India medications pain pills purchase zerit mastercard, rising to 55 per 100 000 men in New Zealand medications kidney failure cheap zerit 40mg line. Higher socio-economic class, smoking, and diets rich in processed meats and low in fibre are thought to be key risk factors. American Cancer Society guidelines on nutrition and physical activity for cancer prevention. Non-smoking, healthy-eating, active-living individuals are less likely to die from colon cancer by a factor of between 2 and 8. There is also some limited evidence to suggest that those who add folic acid or selenium to their diets may have lower rates of colon cancer. Colon cancer is curable in over 80% of patients if caught early, compared with less than 40% if lymph nodes contain metastatic deposits at the time of diagnosis. With this in mind, the National Bowel Cancer Programme was set up as a government initiative to reduce deaths from colon cancer in 2003. Therefore, screening is classically a primary prevention strategy which aims to capture disease early in its course, but it can also involve secondary prevention in individuals with established disease. Examples of screening programmes are blood pressure monitoring in primary care to screen for hypertension, and ultrasound examination to screen for abdominal aortic aneurysm. A positive likelihood ratio quantifies the likelihood of presence of disease if a test is positive; by convention, a positive likelihood ratio 5 constitutes a clinically useful diagnostic test. Conversely, a negative likelihood ratio quantifies the likelihood of absence of disease if a test is negative; a negative likelihood ratio 0. Finally, the safety of the investigation is an important factor, and patient preferences and physician preferences should be taken into consideration. However, while non-invasive screening examinations are preferable from the point of view of patients and clinicians, sometimes invasive screening tests may be required at a later stage in order to give a definitive diagnosis. There is increasing recognition that there are shared risk factors and shared preventive and treatment strategies for vascular disease, regardless of arterial territory. Screening for risk factors for cardiovascular disease Risk factors for cardiovascular disease have been discussed in Chapter 86, and are summarized in Box 351. Primary prevention involves (i) population approaches to address behavioural risk factors. Opportunistic screening for risk factors can form part of both approaches to primary prevention. Different guidelines use different risk stratification tools to predict future cardiovascular risk upon which further management will be based. Guidelines for primary prevention and screening have tended to be pragmatic and based on the availability of infrastructure and resources rather than being evidence based. The total cost of finding a case should be economically balanced in relation to medical expenditure as a whole. As risk factor levels for cardiovascular disease have increased globally in recent years, such considerations will grow in importance. The Global Burden of Disease Study showed that in 2010, the three leading risk factors for global disease burden of mortality and morbidity were high blood pressure (7. It has been hypothesized that a polypill could reduce cardiovascular disease events by 75% in those with vascular disease, which would constitute secondary prevention. If it were used in all those older than 55 years without cardiovascular disease, it is estimated that a polypill would safely reduce ischaemic heart disease events by 88%, and strokes by 80%, which is a primary prevention strategy. Several versions of the polypill are now being trialled by different research groups in different settings involving both primary and secondary prevention. However, these factors must be balanced with the disadvantages of high screening costs and imprecise long-term risk prediction in primary prevention. Risk factor thresholds ignore the fact that the relationship between most risk factors. Moreover, average risk factor levels seen in Westernized societies and in many urban settings in low-income countries may be biologically abnormal, as highlighted by the Global Burden of Disease Study. Advocates of the polypill have suggested that, if the polypill were administered once daily, it could intervene simultaneously across several common risk factors and theoretically reduce cardiovascular disease to a large extent. Amongst people without existing cardiovascular disease, the most discriminatory screening factor is age, because >90% of cardiovascular disease deaths occur in people aged 55 years, as illustrated by multiple national and international epidemiologic studies of cardiovascular disease, including the Global Burden of Disease Study. The use of the polypill in people aged 55 years, especially in those with at least one additional risk factor. It has been estimated that 50% of the decline in cardiovascular mortality observed in developed countries during the last 20 years is attributable to medical therapy. Cardiovascular diseases share risk factors across arterial territories and disease processes, and, occasionally, appropriate and timely recognition and treatment of cardiovascular risk factors can have positive effects on health beyond the cardiovascular system. For example, hypertension is a risk factor for coronary heart disease and stroke as well as atrial fibrillation. Similarly, treatment with aspirin on the basis of increased risk of coronary heart disease may yield benefits in terms of cancer prevention. Screening for risk factors does have costs in terms of human and physical resources, as well as psychological and lifestyle effects on individuals, and is only worthwhile if interventions are possible on the basis of the results of screening tests. For example, government-mandated reductions in salt and saturated fats are examples of national health policies which have been successfully implemented without Box 351. Which interventions offer best value for money in primary prevention of cardiovascular disease Screening for surrogate markers of cardiovascular disease Risk factors are markers that are statistically related to the risk of developing cardiovascular disease; they do not necessarily identify the disease itself. However, surrogate markers of disease make it possible to identify and track disease progression. Reliable markers for the disease might ultimately allow disease progression to replace endpoint events as a guide to the risk of disease and response to therapy, as well as identifying earlier phases of the disease for intervention. Ultimately, the predictive and prognostic accuracy of surrogate markers in screening are weighed against their cost before their use in a given population. Structural and functional changes in the arterial wall precede and accompany atherosclerotic processes. Therefore, measuring arterial stiffness is another way to assess cardiovascular risk. Large-artery stiffness, as assessed by pulse pressure and pulse wave velocity, is age dependent and reflects structural alterations that are accelerated by hypertension and atherosclerosis. These techniques provide a way to identify premature disease and to track the progression of disease and the impact of therapy. This score is a strong predictor of coronary heart disease events and overall mortality, providing predictive information beyond that of standard risk factors across different racial and age groups. It correlates with the presence of coronary atherosclerosis and represents an independent risk factor for coronary events as well as stroke and transient ischaemic attacks. It is an independent predictor of cardiovascular events: when reductions in left ventricular mass result from antihypertensive therapy, they are associated with reductions in cardiovascular events, independently of blood pressure reduction. For stroke and thromboembolism, prevention can be primary (to reduce risk of first stroke) or secondary (preventing recurrent strokes). On the other hand, in the primary prevention of stroke, the three drugs showed some differences in relation to efficacy and bleeding. Thus, it is critical to clarify the level of prevention when considering the impact of different screening and prevention strategies. The area in bold represents people with symptoms of non-anginal chest pain, who would not be investigated for stable angina routinely. Asymptomatic left ventricular dysfunction Asymptomatic left ventricular dysfunction progresses to symptomatic heart failure at rates of up to 10% per year, if untreated. Therefore, early detection, if achievable, is important because randomized trials have shown that appropriate drug therapy can significantly improve survival and cardiovascular outcomes. Because the signs and symptoms of heart failure are so non-specific, many patients who have suspected heart failure and are 1200 referred for echocardiography are not found to have an important cardiac abnormality. A normal natriuretic peptide level has a high specificity; that is, in an untreated patient, it virtually excludes significant cardiac disease, removing the need for echocardiography. Community-based studies have highlighted the high prevalence of heart failure (both systolic and diastolic) in patients with risk factors for cardiovascular disease. However, at present, further trials of targeted echocardiography are required before widespread echocardiographic screening is advocated. Currently, screening strategies have tended to focus on risk factors rather than established disease, due to many factors, including resource constraints, lack of prospective evidence, and sociocultural factors. In addition, the body of randomized evidence in diagnostic and prognostic studies has lagged behind the exponential growth of trials in the therapeutic arena. Given the importance of screening in both high-risk and population approaches to the prevention of cardiovascular disease, more research is urgently needed. Developed in collaboration with American Society of Echocardiography, American Society of Nuclear Cardiology, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. American Heart Association Guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Cardiovascular Disease: Risk Assessment and Reduction, Including Lipid Modification. Summary In this chapter, we have focused on screening for cardiovascular disease via risk factors, surrogate markers, and detecting established disease. While screening has the potential to improve quality of life through early diagnosis and management, it is not an easy process and cannot offer a guarantee of protection. Cystic fibrosis Neonatal screening has helped early diagnosis of cystic fibrosis before any symptoms may have developed and there is evidence to suggest screening provides better pulmonary outcomes. Screening helps affected parents to have genetic counselling to avoid the birth of a second child with cystic fibrosis in a family where the first child may have been undiagnosed. These can lead to long-term psychosocial consequences for the families involved in the screening until further diagnostic testing is done. Carrier screening looking for mutation analysis is available for those who have a relative known to have cystic fibrosis and a relative or a partner known to be a carrier of cystic fibrosis. Prenatal screening trials have been done in the past using different approaches in hospital and primary care settings. Stepwise screening and couple screening methods have been used, with the former first testing the pregnant woman and then only testing her partner if she is found to be a carrier. There is now evidence to suggest that prenatal screening of at-risk couples identified by the newborn screening programme has resulted in a reduction in the live-birth prevalence of cystic fibrosis. Patients should be identified from port of arrival reports, registration with primary care, entry to education, and links with voluntary groups. The main drawbacks of lung cancer screening trials are lack of control for occupational exposures and family history, possible bias from the screening of healthy individuals, and the lack of completely unscreened control groups. This can sometimes lead to over-diagnosis and to patients having to deal with the psychological issues arising from stress and anxiety. The best way of control is preventing the spread from smear-positive cases, and screening contacts. More than 50 000 patients have been enrolled and the results will not be available until later this year. This study has also tried to address some important issues, such as all causes of death in groups screened for lung cancer, the cost-effectiveness of screening, the quality of life for those who test positive, and the influence of screening on smoking behaviour and beliefs. The identification of biomarkers has led to a greater understanding of the molecular pathways of lung cancer. However, despite extensive studies thus far, few have turned out to be useful and, even those used do not show enough sensitivity, specificity, and reproducibility for general use. Recognition of alpha-1 antitrypsin deficiency can prompt specific interventions such as genetic counselling, screening of family members, smoking cessation advice, and consideration of augmentation therapy. Evidence from previous studies suggests that targeted detection has generally produced a higher rate of detecting disease than large-scale population-based screening has. In the future, improved awareness campaigns and easy and cheaper sampling techniques may improve the detection rates, resulting in better treatment options such as augmentation therapy, which may well help preserve lung function in asymptomatic individuals. Individuals can still end up transmitting the mutations to their children but may never acquire the disease due to variable penetrance. One way of screening would be to do genetic testing and counselling of these individuals, with detailed explanation of the limitations and risks involved. Echocardiography should always be performed in cases of suspected pulmonary hypertension. Pulmonary hypertension is defined as a mean pulmonary arterial pressure 25 mm Hg on Doppler measurements but these values can be inaccurate in some individuals. Underestimation of pulmonary hypertension can happen in patients with severe tricuspid regurgitation, and overestimation by >10 mm Hg is also common; hence, Doppler echo is not ideal for screening asymptomatic or patients with mild pulmonary hypertension. Screening and early detection for those with mild or moderate airflow obstruction could benefit from smoking cessation advice and annual influenza vaccination. Pharmacological therapy to these individuals may help prevent exacerbations but may not change hospitalization rates in those with severe disease. It is not known whether pharmacological therapy in patients who are asymptomatic but meet spirometric criteria for moderate-to-severe disease would have the same benefit as in those who are symptomatic with severe airflow obstruction.

Typical symptoms of the disease administering medications 7th edition order zerit 40 mg on line, and less common symptoms Features of the different causes of short stature are given in Table 190 medicine assistance programs order zerit discount. Approach to diagnosing the disease Consistently slow-growing children require full systemic and endocrine assessment medicine 503 order zerit once a day. If the growth velocity (measure in centimetres per year) is normal medicine plus cheap zerit express, there is unlikely to be a significant endocrine disease treatment without admission is known as cheap 40mg zerit with mastercard. If the growth velocity is low symptoms kidney infection buy 40mg zerit otc, without an underlying systemic cause, further investigation is warranted. If there is no gastrointestinal, respiratory, renal, or skeletal abnormality, a cerebral tumour and hypothyroidism must be excluded. Demographics of the disease Organic disease is increasingly found as a cause of short stature; it is found in approximately 50% of cases. Twenty to thirty per cent of non-organic short stature has been attributed to social or environmental factors. Studies have shown that 80% of cases are due to familial short stature, constitutional delay, or both. However, if the presentation includes signs or symptoms suggestive of intracranial pathology, urgent investigation is indicated. Prognosis and how to estimate it If the short stature is due to a systemic disease, treatment of the systemic disease, such a gluten-free diet for coeliac disease, results in complete recovery, and catch-up of lost height will occur. Imaging Skeletal survey A skeletal survey will enable the assessment of bone age: nondominant hand and wrist X-rays allow comparisons that can be used to set standards (this may indicate that sex-steroid priming is required). Treatment and its effectiveness Any underlying systemic illness should be treated. Evidence suggests that this treatment leads to an improvement in quality of life, cardiac risk profile, body composition, and bone density. The aim of treatment for short stature is to correct growth failure and improve body composition. Data has shown an increase in growth velocity in response to treatment but there is some debate over whether there is also an increase in final height. A diagnosis should be made after exclusion of conditions which cause irregular menstrual cycles and androgen excess. Hirsutism that is rapidly progressive and associated with virilization (deep voice, increased muscle size, clitoromegaly, frontal balding) are associated with ovarian and adrenal tumours. Features of associated complications should be recorded, including chest pain, polyuria, polydipsia, high blood pressure, retinopathy, peripheral neuropathy, daytime somnolence, or frequent snoring. Genes involved with insulin and gonadotropin secretion and action and those involved with androgen biosynthesis, secretion, transport, and metabolism are responsible. Ethnic origin, race, and environmental factors also have an influence on the phenotype. A significant number of patients are obese, and the incidence of the condition in different populations parallels the incidence of obesity. In view of persistent unopposed oestrogen stimulation of the endometrium, endometrial hyperplasia or endometrial carcinoma may occur. In a meta-analysis, metformin therapy resulted in ovulation in 46% of patients compared with 24% who received placebo. In women who are resistant to clomiphene citrate alone, addition of metformin may increase ovulation. These should all be discussed in detail with the 621 patient, as will all influence the decisions regarding management. Weight loss Diet and exercise should be recommended, as they may improve frequency of ovulation and fertility and lower diabetes risk and androgen levels. Fertility If fertility is the primary goal, consider clomiphene, metformin and, if these are unsuccessful, gonadotrophins. A history of chemotherapy, radiotherapy, pelvic surgery, or recent infections should be recorded. A review of systems and a full physical examination should be performed, to uncover other autoimmune disorders or genetic causes. Amenorrhoea It is important that women achieve a withdrawal bleed at least once every three months, to reduce the risk of endometrial hyperplasia. The disease develops insidiously and the first sign of the disease may be unexplained Box 191. Aetiology of male hypogonadism the aetiology of male hypogonadism is given in Box 191. Numerous studies have established a close relationship between obesity and low serum free or total testosterone levels in healthy males. An inverse relationship exists between testosterone levels and insulin concentrations in healthy men. Approach to diagnosing male hypogonadism When diagnosing male hypogonadism, enquire about the presence of developmental anomalies associated with the genital tract and elicit features of delayed puberty. If the hypogonadism is post pubertal, establish symptoms of testosterone deficiency. In addition, examine external genitalia for reduced testicular volume or anomalies. Typical symptoms of male hypogonadism, and less common symptoms Common features of male hypogonadism are absence and loss of secondary sexual characteristics; reduced libido; erectile dysfunction; low energy; depressed mood; increased irritability; hot flushes; and decreased muscle strength. Hypogonadism may occur at any age, and hypergonadotrophic hypogonadism is commoner in males. Hypogonadism will manifest differently depending on the time of onset, duration, and severity. If the onset is in prepubertal males, the patient will present with long arms, long legs, sparse body hair (eunuchoidism), and failure to progress through puberty, while, post puberty, erectile dysfunction and infertility are the chief concerning issues, together with non-specific symptoms of lethargy, irritability, and mood changes. Post puberty penile length and skeleton are of normal proportions, hair is of normal distribution but reduced in amount, and patients progressively claim to be shaving less frequently. Complications of low testosterone levels are loss of libido; decreased physical strength; increase in visceral fat; anaemia; and reduced bone density or osteoporosis. In addition, there is an important association with type 2 diabetes mellitus and the metabolic syndrome. Other diagnoses that should be considered aside from male hypogonadism Other diagnoses that should be considered aside from male hypogonadism are Klinefelter syndrome (small testis, gynaecomastia, eunuchoidism), Kallmann syndrome (anosmia, cleft lip or palate, sensorineural deafness), type 2 diabetes mellitus, and metabolic syndrome. Treatment for male hypogonadism, and its effectiveness Testosterone replacement therapy is used as treatment for male hypogonadism, as intramuscular, buccal, and transdermal formulations, as well as gels and implants. It improves well-being, libido, virilization, and sexual function, increases muscle mass, and prevents osteoporosis. Testosterone replacement therapy may also reduce cardiovascular risk by possibly improving markers of insulin resistance in patients with hypogonadism and type 2 diabetes. However, it is contraindicated in prostate or breast cancer and should be avoided in sleep apnoea. In secondary hypogonadism, if fertility is desired, this may be stimulated by pulsatile luteinizing hormone-releasing hormone or gonadotropins. Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. Demographics of prolactinoma Prolactinomas are the commonest functioning pituitary tumour. Microprolactinomas are more common in females and are more common than macroprolactinomas. Aetiology of prolactinoma the causes of hyperprolactinaemia are listed in Box 192. The pathogenesis of prolactinoma is unknown, but the rare malignant prolactinomas may harbour the Ras mutation. Natural history of prolactinoma, and complications of the disease Microprolactinomas are common post-mortem, and less than <17% show an increase in size. In one-third of women with hyperprolactinaemia, the condition resolves after pregnancy or menopause. For macroprolactinomas, dopamine-agonist dose reduction should only be considered >5 years of treatment, as tumour enlargement may occur and definitive treatment may be required (radiotherapy or surgery). Further, patients with macroprolactinomas may develop mass effects such as headaches, visual field defects, hypopituitarism, and invasion of the cavernous sinus; Approach to diagnosing prolactinoma Hyperprolactinaemia is indicated by prolactin levels above the sexspecific normal range. Macroadenomas are spaceoccupying lesions and are sometimes associated with invasion. Typical symptoms of acromegaly, and less common symptoms Symptoms of acromegaly include increased sweating (>80%), headaches, tiredness and lethargy, joint pains, and change in ring size or shoe size. Prognosis for prolactinoma, and how to estimate it Most prolactinomas are treated successfully with medical therapy, with minimal morbidity. Natural history of acromegaly, and complications of the disease Acromegaly is a chronic debilitating disease. The clinical manifestation of acromegaly depends on the chronicity and severity of disease. Thickening of the soft tissue of the hands and feet results in enlargement of ring and shoe sizes. Coarsening of the facial features has a deleterious effect on self-image, markedly affecting self-confidence and quality of life. Local pituitary tumour enlargement may cause headaches and cranial nerve defects; in particular, optic chiasm compression may cause visual field defects (typically, bitemporal hemianopia). There is a two- to threefold increase in mortality in patients with acromegaly, with cardiovascular, cerebrovascular, and respiratory disease contributing to the reduced life expectancy. At diagnosis, 60% of patients have hypertension, arrhythmias, valvular heart disease, and, consequently, diastolic heart failure. In terms of respiratory disorders, upper airways obstruction caused by pharyngeal hypertrophy and macroglossia, with obstructive sleep apnoea, occurs in over 50% of patients. Up to 70% of patients with acromegaly develop large-joint and axial arthropathy due to bone and cartilage overgrowth and periarticular calcification. Clearly, these problems represent the most significant functional disability associated with acromegaly. Tumour compression effects may also cause hypopituitarism in some patients, who may therefore require replacement hormonal therapy. Interestingly, the incidence rate of colon Treatment of prolactinoma, and its effectiveness the aim of treatment for prolactinoma is to restore gonadal function (for both microprolactinomas and macroprolactinomas) and reduce tumour size and prevent expansion (in macroprolactinomas). Medical therapy for the treatment of prolactinoma Dopamine-agonist treatment is the mainstay of treatment for all types of prolactinomas and leads to suppression of prolactin in most patients, so that galactorrhoea ceases and gonadal function returns to normal. Surgery for the treatment of prolactinoma Trans-sphenoidal hypophysectomy for the treatment of microprolactinoma is only indicated in patients who are intolerant to or resistant to dopamine agonists. The surgical cure rate for macroprolactinoma is poor (<30%); therefore, drug treatment should be trialled for all tumours. For microprolactinoma, the surgical cure rate is high (>80%) but the risk of subsequent hypopituitarism is also high (25%), and recurrence occurs at a rate of 4% at 5 years. Radiotherapy for the treatment of prolactinoma Pituitary irradiation leads to a slow reduction of prolactin levels in the majority of patients with prolactinoma. It is useful in the treatment of macroprolactinoma, provided the optic chiasm is not involved. Imaging the thorax and abdomen will also help demonstrate a carcinoid tumour (rare; <1% of cases). Approach to diagnosing acromegaly A high index of suspicion is required to consider a diagnosis of acromegaly. It is useful to ask about changes in appearance; often, patients do not notice, so asking for an old photograph of the patient for comparison and, in particular, asking about changes in ring, shoe, or hat size may be helpful. Biochemical confirmation of the disease should be the initial investigative approach. Prognosis of acromegaly, and how to estimate it If acromegaly is untreated, its mortality is double that of the normal population, with the cause of death usually being cardiovascular, cerebrovascular, or respiratory in origin. Treatment of acromegaly, and its effectiveness Treatment for acromegaly is tailored to the patient. Surgical treatment of acromegaly the first-line management of acromegaly is surgical resection of the pituitary tumour, usually through trans-sphenoidal surgery, although a transfrontal approach may be necessary, depending upon the tumour. More recently, endoscopic endonasal trans-sphenoidal surgery has been shown to be less invasive. Surgery achieves biochemical control in 80% of acromegalics with microadenomas (<1 cm), and 50% of those with macroadenomas.

Furthermore symptoms rotator cuff injury order zerit 40mg on line, it does not prevent new stone formation once the treatment is stopped treatment upper respiratory infection purchase zerit no prescription. It has a reported success rate as high as 90% treatment xdr tb generic 40mg zerit mastercard, although it is more successful in patients with few medicine youth lyrics discount zerit 40mg with mastercard, small non-calcified gallstones treatment that works zerit 40 mg line. Typical symptoms of gallstones medicine gustav klimt buy zerit from india, and less common symptoms Gallstones are asymptomatic in the majority and are often coincidental findings. Pain related to the gall bladder or biliary tree is usually constant and located in the upper abdomen (right upper quadrant or epigastrium) and is worsened by eating, especially fatty meals. The nature of the pain can vary, being described as a dull, gnawing, aching, band-like burning or tightness. Simple gallstones often cause mild-to-moderate pain, whereas cholecystitis or cholangitis can produce a more severe pain lasting for days. Biliary pain can radiate through to the back or be referred to the right shoulder or scapula, and can be associated with nausea and vomiting. Cholangitis is more likely to be accompanied by signs of sepsis, including fever, tachycardia, and hypotension. Jaundice will only be seen when there is an obstructed biliary tree causing a blockage to the flow of bile. Analgesia should be given: opiates are often necessary, although morphine should be avoided as it can increase sphincter of Oddi tone. Anticholinergic antispasmodics (dicyclomine, Buscopan) can be useful for biliary colic. Gall bladder distension can be effectively treated with anti-inflammatory drugs (indomethacin). Although bacterial infection only complicates 20% of cases, antibiotics are usually given to all patients with cholecystitis. However, commonly used antibiotics include penicillin or cephalosporin plus metronidazole, or piperacillin and tazobactam. Cholecystectomy should be performed on all patients with complications from gallstones, as gallstones have a high risk of recurrence (~70%). However, it is no longer performed during an acute attack of cholecystitis, unless complications develop (perforation, gall bladder gangrene). If a cholecystectomy is performed for acute cholecystitis, it is preferable for it to be performed immediately once the diagnosis has been established. Following admission, the inflammation will often progress, making a laparoscopic procedure more difficult, and more often requiring conversion to an open procedure. Emergency drainage of a distended gall bladder can be performed using a radiologically placed drain. Cholecystectomy is usually performed when the patient has fully recovered from the cholecystitis, on an elective basis. The highest prevalence is in fairskinned Northern Europeans, and gallstones are more common in females. It has been proposed that the reason for the female preponderance is oestrogens causing increased cholesterol secretion and progesterone promoting biliary stasis. Other risk factors include obesity, rapid weight loss, diabetes mellitus, haemolysis. Natural history of gallstones, and complications of the disease Seventy per cent of patients with asymptomatic gallstones will have no complications. The majority of patients with complications related to gallstone will recover with standard therapy. Seventy per cent of patients would have suffered with a recurrence of their symptoms, 654 Treatment of cholangitis Cholangitis treatment mirrors that of acute cholecystitis. However, since its aetiology is due to a blockage in the biliary tree, treatment is required to relieve this. Botulinum toxin, injected endoscopically into the sphincter, can give relief of symptoms, and the procedure is relatively easy to perform. Response to botox can also be used to predict those who will respond to a sphincterotomy. Biliary dyskinesia, causing a motor abnormality of the sphincter of Oddi, has been considered, and would correspond with studies that have shown increased frequency of phasic contractions, retrograde propagation of contractions, and a paradoxical response to cholecystokinin. Cholesterol polyps are the most common (70%), and other types of polyps include inflammatory polyps, hyperplastic polyps, lymphoid polyps, fibrous polyps, granulation tissue, and adenomas. Large polyps may cause abdominal pain, which is thought to be due to hypercontraction of the gall bladder, or intermittent obstruction of gall bladder emptying. Demographics of gall bladder polyps Benign gall bladder polyps affects all ages equally. They are slightly more common in men and in patients of Indian origin, with an increased incidence in patients with primary sclerosing cholangitis and hepatitis B. Patients suffer with biliary-type pain, as described, with no structural abnormalities to explain their symptoms. Natural history gall bladder polyps, and complications of the disease the main concern with polyps is the adenoma-to-cancer sequence which is seen in colonic adenomas. Polyps <5 mm are unlikely to be malignant, whereas those >15 mm have a much higher risk; for this reason, gall bladder polyps should remain under surveillance. Treatment of gall bladder polyps, and its effectiveness Generally, gall bladder polyps 1. It is characterized by oedema and necrosis of peripancreatic fat and may progress to necrosis of glandular and surrounding tissue. Activation of pancreatic enzymes leads to pancreatic autodigestion and systemic effects. Typical symptoms of acute pancreatitis, and less common symptoms Pancreatic pain is classically described as epigastric in origin, radiating through to the back, and worsened by lying down or eating. Patients with acute pancreatitis usually have severe pain, which is relieved only by opiates, and are often systemically unwell, with fever, tachycardia, dehydration, and leucocytosis. Demographics of acute pancreatitis Acute pancreatitis has an annual incidence of 2 per 100 000 population, with an increasing incidence with age. Severe inflammation can lead to the systemic inflammatory response syndrome and multi-organ failure. Infected pancreatic necrosis has a mortality reaching almost 100% if not debrided. Ultrasound may show inflammation of the pancreas and is especially good for identifying biliary obstruction or gallstones. Liver function tests should be checked, as the vast majority of patients have a history of excess alcohol consumption, and these results may confirm concurrent hepatic damage, inflammation, and synthetic function. Calcium and triglyceride levels also should be checked to ensure they are not etiological factors for acute or chronic pancreatitis. Prognosis of acute pancreatitis, and how to estimate it Amylase and lipase levels have no prognostic role in pancreatitis. The Ranson and Glasgow scoring systems have been used in the past, but can only be applied at 48 hours. A score of >8 at initial presentation or 24 hours later is considered in keeping with severe pancreatitis. Approach to diagnosing acute pancreatitis the differential diagnosis of any patient presenting with acute abdominal pain and with an underlying history of excess alcohol consumption should include acute pancreatitis. Diagnostic tests for acute pancreatitis A rise in the serum amylase level, which peaks in the first 24 hours of acute pancreatitis, combined with clinical signs and symptoms, is virtually diagnostic of acute pancreatitis. Fluid resuscitation is integral to restore intravascular volume and third-space losses, with placement of a urinary catheter 656 Table 201. Genetic studies have suggested several genetic mutations may be associated with hereditary and idiopathic chronic pancreatitis. Typical symptoms of chronic pancreatitis, and less common symptoms Chronic pancreatitis can present with constant discomfort, or with recurrent episodes of severe pain. Persistent pancreatic destruction may lead to the patient presenting with symptoms of exocrine insufficiency (diarrhoea and/or weight loss) or endocrine insufficiency (diabetes). Demographics of chronic pancreatitis Chronic pancreatitis affects men twice as often as women and is more common in the fourth to the sixth decades. Natural history of chronic pancreatitis, and complications of the disease the natural history of chronic pancreatitis is highly variable, but the overall survival is approximately 70% at 10 years and 45% at 20 years. In the majority, the pain will gradually resolve or reduce over the course of years to decades, although, in alcohol-related disease, abstinence may expedite pain relief. Endocrine dysfunction may lead to a reduction in insulin secretion and subsequent diabetes, with all associated complications. The exocrine pancreas produces digestive enzymes, including trypsin, chymotrypsin, lipase, and amylase, and lack of these leads to malabsorption and resultant diarrhoea, steatorrhoea, and/or weight loss. However, nutritional deficiencies are not seen until 90% of exocrine function is lost. Patients with moderate-to-severe pancreatitis, or any suggestion of organ failure (respiratory, circulatory, renal, etc. Those with milder disease should still have close monitoring in view of the risk of rapid deterioration. Nutrition is extremely important, given the hypercatabolic state of the patient; usually, nasojejunal feeding is implemented early via endoscopically placed nasojejunal tubes. Total parenteral nutrition is an alternative, particularly in patients who develop an ileus. However, the higher costs and increased rate of septic complications preclude the routine use of parenteral nutrition. The use of antibiotics in acute pancreatitis is contentious, with studies showing variable results, and recognition of the increased risk of developing antibiotic-resistant bacterial strains. Fine-needle aspiration of the necrotic area can be cultured and used to guide antibiotic therapy. In general, sterile necrosis will be treated conservatively, whereas infected pancreatic necrosis requires surgical debridement by open surgical techniques. However, minimally invasive procedures (laparoscopic or endoscopic) may hold promise for the future. Approach to diagnosing chronic pancreatitis Chronic pancreatitis is less straightforward, since the pain is often chronic, but an alcohol history may be a clue to the diagnosis. The presence of symptoms of pancreatic insufficiency (diarrhoea or diabetes) may help confirm chronic damage to the organ. Diagnostic tests for chronic pancreatitis Amylase is less useful in chronic pancreatitis as there is often no rise in serum levels, due to atrophy and fibrosis, with overall destruction of exocrine cells which normally produce this enzyme. Chronic pancreatitis is often diagnosed on the clinical history of recurrent abdominal pain, commonly in a setting of alcohol excess. Anterolateral and oblique views should be performed to ensure the vertebral column does not conceal small calcifications. Pancreatic exocrine insufficiency can be assessed by a taking a stool sample to measure faecal pancreatic elastase. This will be reduced in advance pancreatic exocrine insufficiency (loss of 90% exocrine function). As with acute pancreatitis, liver function tests, calcium levels, and triglyceride levels should be checked. Chronic pancreatitis Chronic pancreatitis is characterized by progressive inflammation and fibrosis, leading to the irreversible loss of pancreatic structure and function. Aetiology of chronic pancreatitis Sixty to eighty per cent of cases of chronic pancreatitis are related to alcohol and, conversely, 10% of alcoholics develop chronic pancreatitis. Analgesics are required for pain relief; often, simple analgesics do not suffice and opiates are required. In extreme cases, a celiac ganglion block can relieve pain in ~50% of patients, but the relief is often short term, and complications (haemorrhage, transverse myelopathy) preclude regular use. Vitamin supplements (especially vitamin B12) should be given where necessary, and low-fat meals may reduce symptoms. Pancreatic duct strictures can be treated endoscopically by stent insertion and sphincterotomy, with resolution of pain in 65%. Surgical procedures include a pancreaticojejunostomy to relieve pancreatic duct obstruction, or a pancreatic resection. However, the operative mortality is 3% and 10%, respectively, so it is reserved for patients who are severely affected but have an otherwise healthy premorbid status. First, this can confirm the diagnosis, but the treatment also can relieve symptoms, improve structural abnormalities, and improve endocrine function in the short term. Steroids have been shown to help biliary strictures biochemically and structurally, although many patients undergo endoscopic therapy for biliary strictures before the diagnosis is confirmed. Diabetes Type 1 diabetes mellitus is caused by the autoimmune destruction of pancreatic beta cells, which normally produce insulin. Cystic fibrosis Cystic fibrosis is a condition caused by abnormalities in exocrine gland function and leads to the production of thick secretions affecting the lungs in 90% of patients with cystic fibrosis. Subsequently, symptoms are in keeping with those of acute pancreatitis, and also include jaundice and weight loss.

Other commonly used forms of radiotherapy include brachytherapy symptoms yellow fever cheap 40mg zerit free shipping, which is the placement of radioactive sources at the site for treatment medicine with codeine 40 mg zerit sale. Endocrine therapy in the form of tamoxifen and treatment 4s syndrome purchase zerit 40mg with amex, more recently medications for high blood pressure cheap zerit 40mg overnight delivery, aromatase inhibitors also plays an important role in the adjuvant therapy of hormone-responsive breast cancers medications lexapro discount zerit 40mg online, reducing recurrence rates and improving overall survival medications ordered po are buy zerit in india. Palliative chemotherapy Cytotoxic chemotherapy, as a systemic treatment, has the theoretical advantage of being able to treat all sites of metastatic disease simultaneously and has an established role in the management of advanced malignancy. Endocrine therapies are also commonly used as palliative treatments for hormone-responsive advanced breast cancer and prostate cancer, producing significant clinical benefits without the toxicity often associated with cytotoxic chemotherapy. Newer therapies Surgical advances and other local therapies Conventional surgical techniques are constantly evolving with the development of new technology, for example minimally invasive surgery, with the aim of reducing surgical morbidity while maintaining or improving oncological outcomes. These include cryotherapy, most commonly used for locally recurrent prostate cancer, and radiofrequency ablation. Palliative radiotherapy Radiotherapy is an effective palliative treatment for symptom control in advanced malignancy. Occasionally, higher radiotherapy doses are appropriate to attempt to maintain local disease control for as long as possible and hopefully prevent unpleasant symptoms from developing if the prognosis and clinical situation suggest this may be a potential problem. Advances in radiotherapy While the basic principle behind radiotherapy remains the same today as always, technological advances in the delivery of radiotherapy are allowing improvements in the therapeutic ratio for various malignancies. Intensity-modulated radiotherapy, for example, allows the delivery of more complicated distributions of radiation dose (including concave volumes) to the intended target, while avoiding high doses to adjacent organs and thereby reducing toxicity. This ability has been utilized in prostate cancer to reduce rectal and urinary toxicity and in head and neck cancer to reduce xerostomia from salivary gland irradiation, while maintaining efficacy. A variety of techniques using both conventional linear accelerators and alternative equipment. Progress in the imaging techniques associated with radiotherapy will also allow improved accuracy of target definition and compensation for organ movement. The vast majority of external beam radiotherapy is currently administered with photon beams (X-rays). There is a developing interest in replacing photons with protons and perhaps even heavier charged particles to take advantage of specific physical characteristics of their depth dose curves, allowing the delivery of a high dose of radiation to a tightly defined volume while sparing adjacent structures. In addition to having these dosimetric advantages, certain charged particle beams, such as carbon ions, also possess some biologic advantages in terms of tumour kill potential. With advances in modern cellular biology, it is now possible to design conjugates that direct radioisotopes to particular cellular targets. An example of such a targeted radiopharmaceutical that Cytotoxic chemotherapy and endocrine therapy Radical and adjuvant chemotherapy In terms of radical therapy, cytotoxic chemotherapy is the third most important modality of treatment and is only curative in isolation for haematological malignancies and germ cell tumours which are exquisitely chemosensitive. In terms of numbers, cytotoxic chemotherapy plays a much more significant role as an adjuvant therapy for solid tumours to reduce the risk of recurrent disease following primary therapy (usually surgery). The best examples of this are adjuvant chemotherapy for breast cancer and colon cancer. As we gain a greater understanding of the underlying cellular basis of cancer, further targets and associated therapies will undoubtedly be developed and added to the therapeutic options available for a variety of cancers. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 2. Prospects for combining targeted and conventional cancer therapy with immunotherapy. When diagnosed early, it has a high chance of cure with surgery, external beam radiotherapy, or brachytherapy. Demographics of the disease Like the prostate gland from which it arises, prostate cancer is exclusively a male disease. The disease is rare in those below the age of 40, and only 15% of patients are diagnosed below the age of 65. Post-mortem studies in men dying from other causes show that, by the age of 80, 70% of men will have at least microscopic evidence of prostate cancer. Aetiology of the disease the mechanism of transformation from normal prostate cells to cancer is poorly understood but appears to have a hormonal basis, with androgen stimulation playing an important role in the pathogenesis. Approximately 75% of prostate cancers arise in the peripheral zone of the gland, with the remainder arising in the central and transitional zones. Many prostate cancers are multifocal, arising synchronously within different parts of the prostate. Histologically, over 95% of prostate cancers are adenocarcinomas, derived from prostatic acinar cells. Natural history, and complications of the disease Without treatment, the natural history of the disease is variable. Given that many patients who develop the disease are elderly, it is not difficult to see why more prostate cancer patients die of other causes than from their cancer. Rarer but recognized symptoms include incontinence, impotence, haematuria, and haematospermia, all of which are suggestive of more locally advanced disease. Sites of bony involvement include, in decreasing order of frequency, the lumbar spine, the proximal femur, the pelvis, the thoracic spine, the ribs, the sternum, and the skull base (which typically presents with cranial nerve palsies). Compared to the case with other malignancies, the spread of prostate cancer to the liver and the lungs is a relatively rare and late event. It is also helpful in identifying seminal vesicle invasion and enlarged local lymph nodes. Levels above 10 correlate with presence of prostate cancer in up to two-thirds of cases. Other relevant investigations Nuclear medicine bone scan A nuclear medicine bone scan is used to determine the presence and location of skeletal metastases. A bone scan should be performed in all patients with intermediate or high-risk disease (see Table 326. In the absence of bone pain, a bone scan is not routinely indicated in patients with low-risk disease. Gleason score the Gleason score is a histological grade based on the Gleason grade, which allocates tumours a value between 1 and 5, based on the glandular architecture. A Gleason grade of 1 represents a nearnormal glandular pattern, while a grade of 5 represents the more aggressive end of the spectrum, with no clear glandular pattern. The Gleason score is the sum of two Gleason grades: the predominant pattern and the second most common pattern. For men with high-risk disease, while long-term cure is still possible, there is a higher likelihood that the cancer will either progress or spread. Treatment and its effectiveness Prevention There is currently no treatment licensed for the prevention of prostate cancer. Finasteride is an anti-androgen which inhibits the enzyme 5-alpha reductase, thereby blocking the metabolism of testosterone to the more potent androgen, dihydrotestosterone. Despite the not-insignificant toxicity profile that includes impotence, loss of libido, and ejaculatory difficulties, the trial did demonstrate an impressive 24. Of note, however, is that, of those men who did go on to develop cancer, there was a higher proportion of high-grade cancers in the finasteride arm. This risk stratification is also helpful in guiding both imaging investigations and in formulating recommendations for treatment. While strong evidence exists that prostate cancer screening is effective in diagnosing more cancers, controversy remains over what impact, if any, detecting more prostate cancers would have on the more important endpoint of improving overall survival. Two large screening trials set up to address this question have recently reported conflicting outcomes. There is ongoing research aimed at reducing the number of treatments even further using stereotactic body radiotherapy. Side effects of radiotherapy can be divided into acute side effects (predominantly urinary symptoms, rectal discomfort, bowel symptoms, and fatigue), which generally settle within a few weeks of finishing the treatment, and long-term side effects, which are frequently permanent. Other long-term side effects include proctitis (which occurs in approximately 5% or patients), incontinence (which occurs in less than 5% of patients), and long-term changes in bowel habit. In patients with intermittent or high-risk disease, hormonal therapy is usually given in combination with radiotherapy. Pelvic radiotherapy can be considered for patients with a high risk of pelvic lymph node involvement. Treatment of early stage prostate cancer Early stage prostate cancer, where the disease is confined to the prostate gland, is potentially curable. Radical prostatectomy, radical radiotherapy, and brachytherapy, along with active surveillance, all have a role in the curative treatment of prostate cancer (Table 326. There are no randomized trials comparing these treatments head to head; in the absence of these, side effect profiles play an important role in clinician recommendations and patient choice. Watchful waiting While so-called watchful waiting should not be regarded as a curative treatment, it is appropriate for some patients. Watchful waiting is the conscious decision not to treat until patients develop symptoms, at which point they are usually treated with hormone therapy. It is particularly suitable for patients with a short life expectancy, such as the elderly or those with significant comorbidities, as these patients are unlikely to die from prostate cancer. Brachytherapy Brachytherapy is a form of radiotherapy in which the radiation is delivered directly to the prostate using radioactive sources. Two different techniques are used: permanent implantation of radioactive seeds (low-dose-rate brachytherapy) or temporary implantation of radioactive wires (high-dose-rate brachytherapy). Brachytherapy has a relatively favourable side effect profile, causing lower rates of impotence and incontinence than surgery or external beam radiotherapy but higher rates of obstructive and irritative urinary symptoms. In men with intermediate or high-risk disease, combined treatment with highdose-rate brachytherapy and external beam radiotherapy can be considered. It should be considered in patients who have low-grade tumours and are fit enough to undergo a radical treatment in the event of disease progression. This approach can delay and, in some cases, avoid altogether the risks and side effects of a radical treatment. Radical prostatectomy Radical prostatectomy involves the complete resection of the prostate along with the seminal vesicles. Various surgical techniques for this exist, including open retropubic or perineal approaches and laparoscopic or robotically assisted techniques. In appropriately selected patients, mortality is less than 1%, but major morbidity may be as high as 10%. Cryotherapy and high-intensity focused ultrasound Cryotherapy and high-intensity focused ultrasound are new techniques that aim to eradicate prostate cancer by freezing or heating the gland, respectively. They are not currently recommended outside the context of clinical trials, as there is an inadequate amount of longterm outcome data. Treatment of advanced prostate cancer Advanced or metastatic disease is, by definition, incurable, and the aim of treatment is therefore to prolong survival and relieve symptoms. In this section, some of the more commonly used treatments for advanced prostate cancer will be discussed. Each has slightly different indications; therefore, not all drugs will be suitable for every patient. The sequencing of the drugs is individualized based on patient and disease characteristics. Side effects include tiredness, nausea, vomiting, hair loss, and bone marrow suppression (along with the accompanying risk of neutropenic sepsis). Palliative radiotherapy Radiotherapy plays an important role in the management of bone metastases. Pain caused by metastases usually responds very well even to a single fraction of radiotherapy. Radiotherapy is also indicated following surgical fixation of pathological fractures or spinal surgery. Hormone therapy Prostate cancer growth is dependent on the presence of testosterone. These drugs stimulate the production of testosterone in a non-pulsatile (non-physiological) manner, resulting in a disruption of the endogenous hormonal feedback systems and the subsequent downregulation of testosterone production. Recently, a luteinizing hormone-releasing hormone antagonist called degaralix has been introduced; it directly blocks the pituitary axis, thus avoiding the initial stimulation of androgen production and negating the need for initial anti-androgens. They have a role in the treatment of osteoporosis, which is a long-term side effect of androgen deprivation, and in the control of pain associated with metastatic bone disease. Bone-seeking radioisotopes Administration of bone-seeking radioisotopes can be helpful in a subset of patients, to control widespread symptomatic osteoblastic bone disease when the disease no longer responds to hormonal manipulation. The use of radium-223 in this context is associated with a small increase in life expectancy. Immunotherapy Sipuleucel-This a personalized cell-based cancer vaccine licensed for the treatment of prostate cancer.

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