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Radiological investigations and bone marrow biopsy are performed to determine the extent of disease in order to define the Ann Arbor stage (see Staging and risk stratification) arteria jugular generic aceon 4mg with mastercard. Staging via the Ann Arbor classification involves a thorough history to detect presence of B-symptoms (Table 32 arrhythmia update buy 8 mg aceon mastercard. However blood pressure medication chart cheap aceon uk, some centres still perform bone marrow biopsy in these cases due to the significant implications if bone marrow involvement is identified blood pressure chart and pulse rate purchase aceon 8 mg otc. Importantly, the criteria used to define favourable and unfavourable are not standardized between groups, and whilst the criteria are similar, there are important differences. Of note, both of these risk stratifications are assessed on baseline features of disease. A strategy that is currently under evaluation is the assessment of risk based on the early response to therapy. In addition, there have been improvements in staging techniques with more accurate radiological delineation of involved sites, more effective chemotherapy and other improvements in radiotherapy techniques (including shielding and advances in planning technology). The aim of this strategy is to offer escalated therapy to those patients with suboptimal initial disease response, whilst sparing those patients with good early disease control potentially unnecessary further treatment/toxicity. Relapsed/refractory disease For patients that relapse or who are refractory to primary therapy, the traditional treatment paradigm has been to administer salvage chemotherapy, choosing agents that were not administered in frontline treatment. Data from early trials suggest that this strategy results in approximately 50% disease-free survival at 3 years. The most potent determinant of outcome after autologous stem cell transplantation is the degree of chemoresponsiveness to salvage treatment. Studies have shown an overall response rate of approximately 75% and approximately onethird of patients achieving complete remission in a heavily pretreated patient cohort. It is also useful in the palliative setting for relapsed patients post autologous stem cell transplantation. The most common secondary malignancies are breast, lung and gastrointestinal tract cancers. Radiotherapy increases the risk of secondary solid organ malignancy at exposed sites, whereas chemotherapy has a more complex association with secondary solid organ malignancy, resulting in an increased risk of some types. One of the most potent determinants of the risk of developing a secondary solid organ malignancy is the age at which the patient received treatment. In contrast, the risk of breast cancer in patients treated at age 40 and over is similar to that of the general population. The explanation for this is likely to be a mixture of increased vulnerability of developing breast tissue to the transforming effects of radiotherapy, and a longer duration of ovarian function post treatment. Of note, however, these estimates of risk are based on older-style radiation fields and radiotherapy techniques. The risk of subsequent breast cancer (and indeed most cancers) is related to the radiotherapy dose and field size. The risk of lung cancer is increased in those receiving lung exposure and patients should be counselled to cease smoking. In addition, elderly patients may be at particular risk of specific chemotherapy side-effects such as bleomycin lung toxicity. Chemotherapy regimens utilizing conventional cytotoxic agents have been specifically developed for use in this group. Given the poor outcomes, novel approaches are particularly attractive in this group of patients. Substitution of conventional chemotherapy agents with novel agents in frontline treatment. During the first 10 years after diagnosis, most deaths are the result of relapse, however, after this period most deaths are a result of late effects of treatment. The reason for this is not clear, but it has been hypothesized to be due to the lower use of radiation in later trials, as well as exposure to fewer cycles of chemotherapy. This is contributed to by exposure of the heart to radiotherapy, as well as treatment with anthracyclinebased chemotherapy regimens. The types of cardiovascular disease that may occur include premature coronary-artery disease, myocardial infarction, congestive cardiac failure, valvular heart Chapter 32 Hodgkin lymphoma disease, conduction abnormalities. The latency of coronary artery disease as a result of radiotherapy is approximately 10 years. Importantly, concomitant cardiovascular risk factors including hypertension, hypercholesterolemia and smoking all compound this risk and should be aggressively managed. For male patients, sperm storage can usually be offered before treatment, whereas fertility-sparing measures in female patients are time consuming and, because of treatment delays, not always advisable. A truly enviable situation when compared to many other haematological and non-haematological malignancies. The onus is now on the managing clinical team to deliver this curative therapy in a manner commensurate with individual patient risk in order to minimize the risk of acute and long-term morbidity and mortality. This will be best achieved by a multidisciplinary approach, including both radiation oncologists as well as haemato-oncologists. Whilst the low-grade lymphomas have distinct epidemiology, pathogenesis, morphologic, immunophenotypic and clinical features, they share a broadly similar disease course characterized by slow rate of growth and long median survival, with the possible exception of mantle-cell lymphoma, which frequently has a more aggressive course. In the majority of cases, these are incurable malignancies and whilst the progress is usually slow, the development of refractory disease, or transformation to high-grade disease can occur in all subtypes. Since the previous edition of this book there have been advances in the understanding of the pathogenesis of lymphoma and new therapies are emerging that show great promise. It is not clear why there was a rise in incidence, but it is likely that changes in medical practice, reporting conventions, and changes to the classification of lymphomas have had an impact. Numerous studies investigated possible links to environmental agents such as pesticides or industrial exposures, but no firm associations have been identified.
To date blood pressure young male discount aceon 8 mg with mastercard, treatment has aimed at reducing the platelet destruction pulse pressure 72 buy aceon 8 mg line, mainly through immunosuppression blood pressure medication beta blockers side effects proven 4mg aceon. These recent targeted treatments are likely to be associated with less toxicity than older therapies hypertension 150 70 buy aceon cheap online. The profound thrombocytopenia may be associated with extensive petechiae, purpura and bruises. Despite the severity of the clinical features, most children need little treatment, and undergo spontaneous remission in the majority of cases. In adults there is generally no prodromal illness and the patient may be aware of petechiae or excessive bruising, and seek medical attention. Many patients suffer few clinical problems related to their thrombocytopenia, while others have major bleeding from the outset. In addition, there may be an acquired platelet dysfunction caused by antibody binding to an important region of the glycoprotein molecules on the platelet surface. For some it implies the postsplenectomy patient who has failed to respond or who Postgraduate Haematology, Seventh Edition. These are disorders in which there are antibodies or cells (B cells, T cells, antigen-presenting cells, or others) that react against selfantigens. The binding of antibodies to target cells results in clearance of the antigen from the body. The normal adaptive response, such as that seen in microbial infection, results in complete removal of the non-self-antigen. In autoimmune disease, however, there is continual production and incomplete clearance of the antigen, leading to perpetuation of the immune attack. Others interpret the term to mean those who do not respond well to treatment irrespective of splenectomy status. These have been published and will be used in all drug trials, and in the clinic, from now on. Autoimmune disease arises only when all these determinants are present in an individual at the same time. This is further reinforced by the observation that self-reactive lymphocytes are commonly found in normal individuals. Opsonized platelets are removed prematurely by the reticuloendothelial system via an Fc-dependent mechanism. In addition, the autoantibodies may impair megakaryocyte growth and development, platelet release and may also induce apoptosis of megakaryocytes. Looking for the presence of platelet-associated IgG is of no value since this is found in non-immune as well as immune thrombocytopenia. It has also been implicated in the development of gastric adenocarcinoma and mucosa-associated lymphoid tumours, and in some autoimmune disorders. However, the data from different studies are conflicting, with some centres showing a very high rate of response to eradication, while others have a low rate. Possibilities include molecular mimicry, where there is crossreactivity between the antibody, the bacterium and platelet antigens. The greater this level, the more the bone marrow is driven to produce increased numbers of platelets. A full physical examination should be normal, apart from the expected clinical signs associated with thrombocytopenia. Enlargement of the liver, spleen or lymph nodes suggests an alternative diagnosis. There may be a degree of iron deficiency anaemia, but this should be in proportion to the clinical history. It is not clear which patients require treatment, whether treatment has any major beneficial effect on the patient, whether patients live longer or whether treatment alters the natural history of the disease. There have been a few studies published looking at clinically relevant bleeding and platelet count. In normal individuals, there is a correlation between the platelet count and bleeding. A thorough history should be obtained, looking for 776 Chapter 42 Primary immune thrombocytopenia Table 42. Bone marrow examination Previously, one of the mainstays of diagnosis was assessment of the bone marrow. The rationale behind this was the possibility of a patient having a marrow disorder such as leukaemia, lymphoma or infiltration. However, studies to date have shown quite clearly that in patients with isolated thrombocytopenia, and with no atypical symptoms or signs, no cases of bone marrow pathology were detected. If patients fail to respond to , or relapse following, first-line treatment, then a bone marrow examination should be carried out. Finally, a bone marrow examination should possibly be carried out if splenectomy is being contemplated (Table 42.
The biggest risks to such patients are hypertension blood pressure medications with the least side effects 2mg aceon visa, strokes and cardiovascular complications prehypertension need medication discount aceon 4 mg mastercard. Patients who remain polycythaemic despite such treatments should be treated with repeated venesections to maintain their haematocrit below 0 blood pressure drop order 4 mg aceon visa. The commonest reported ones are hepatocellular carcinoma blood pressure medication diltiazem buy aceon with amex, cerebellar and other haemangiomata and large uterine fibromyomata. Endocrine disorders the mechanism underlying the development of polycythaemia in most endocrine disorders lies in the over-production of androgens, which can produce polycythaemia by increasing Epo levels and also, probably, through a direct action on bone marrow progenitors. Uncontrolled diabetes is also an important cause, which is usually easily identified. With the advent of increasingly sophisticated diagnostic tests and the identification of the molecular lesions in many inherited forms of polycythaemia, idiopathic erythrocytosis is becoming a rare entity. These patients are usually treated with low-dose aspirin unless this is contraindicated and venesection instituted to a target of 0. Apparent polycythaemia Apparent polycythaemia refers to a raised haematocrit in the presence of a normal red cell volume (less than 25% above the predicted mean normal value). Smoking, hypertension, obesity, excessive alcohol and diuretic therapy have all been associated with apparent polycythaemia. It is not clear whether apparent polycythaemia is associated with increased rates of thrombosis, but it seems sensible to encourage affected individuals to avoid known predisposing factors. There are no convincing data that routine venesection is beneficial, but a haematocrit beyond 0. In 1934 Epstein and Goedel first described a patient with persistent elevation of the platelet count in association with megakaryocyte hyperplasia and tendency for venous thromboses and haemorrhage. The commonest are a 52-bp deletion, so-called type-1 mutation, or a 5-bp insertion, so-called type-2. Patients lacking all three mutations (triple-negative) are often young and also have a lower thrombosis risk. The best characterized are aged over 60 years and have a prior history of thrombosis. The exact role these and other predictors have in individualizing treatment regimens remains unclear. Efforts to correlate the thrombotic risk to platelet function abnormalities have generally been fruitless and this investigation is also unable to predict haemorrhagic risk. Bleeding is, however, more common in patients with platelet counts above 1000 and, in at least some cases, this is due to an acquired von Willebrand disease, with a decrease in circulating high-molecular-weight multimers caused by adsorption to the surface of the excessive platelets. Routine testing for acquired von Willibrand disease is not generally recommended, however. Mutation-negative patients do nonetheless exhibit many clinical and laboratory features characteristic of a myeloproliferative neoplasm, including the presence of endogenous erythroid colonies and a risk of transformation to acute leukaemia. Some, but not all, cases of apparent polycythaemic transformation may represent resolution of prior iron deficiency, as can happen with iron supplementation and after the menopause. The insidious onset of myelofibrotic transformation and the reluctance to serially study bone marrow trephine biopsies have hampered attempts to define its nature and frequency. Nonetheless, recent studies have shown that progression of reticulin levels over time shows extensive interindividual variability, and can be influenced by choice of therapy, being more marked in patients treated with anagrelide (see below). The presence of cytogenetic abnormalities and treatment with alkylating agents increase this risk. In particular, studies of interobserver reliability for the histological component of this classification have shown it to be poorly reproducible, and a prospective multicentre study of the prognostic discrimination achieved by such a label found it to be minimal. Nevertheless, bone marrow histological features such as giant, multilobated megakaryocytes and megakaryocyte clustering (Figure 26. Reactive thrombocytosis Thrombocytosis is most commonly reactive and secondary to increased levels of circulating cytokines that stimulate thrombopoiesis. Inflammatory, vasculitic and allergic disorders, acute and chronic infections, malignancies, haemolysis, iron deficiency and blood loss can all lead to an increased platelet count (Table 26. Other clonal thrombocytoses A number of other haematological malignancies can be associated with thrombocytosis. Iron deficiency can mask the typical raised 483 Postgraduate Haematology coexisting cytopenias, dysplastic features or specific cytogenetic abnormalities. High-risk patients High-risk patients are those over 60 years old and those with one or more high-risk features, i. In high-risk patients, control of the platelet count with hydroxycarbamide reduces thrombotic events compared to no cytoreductive therapy. Patients receiving anagrelide plus aspirin were significantly more likely to reach the composite primary endpoint (arterial thrombosis, venous thrombosis or major haemorrhage) and more likely to discontinue their allocated treatment. Compared to hydroxycarbamide plus aspirin, treatment with anagrelide plus aspirin was associated with a significantly increased rate of arterial thrombosis, major haemorrhage and myelofibrotic transformation, but a decreased rate of venous thromboembolism. These results suggest that hydroxycarbamide plus aspirin should remain first-line therapy for high-risk patients. Anagrelide is a useful secondline agent, but the decision to use concurrent aspirin should depend on the relative risks of arterial thrombosis and haemorrhage in the individual patient.
Pathophysiology of lysosomal storage disorders In most lysosomal storage disorders blood pressure 4 year old order 4mg aceon with visa, an inherited deficiency of a specific lysosomal enzyme results in the accumulation of undegraded substrates within the lysosome blood pressure procedure order aceon with paypal. In others blood pressure chart jnc 4 mg aceon with mastercard, accumulation of storage product results from deficiency or malfunction of activator proteins or transport proteins blood pressure reading 400 safe aceon 4mg. Individual mutations of the relevant genes give rise to variable levels of residual enzyme activity. The resulting diseases are grouped according to the major stored substance, for example the mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Storage product within the lysosomes causes disruption of cellular organization and disturbance of normal membrane functions including signal transduction and ion transport. Different lysosomal storage diseases have the characteristic organ distribution patterns of the stored metabolites. However, even within a discrete storage disorder there are often wide-ranging clinical manifestations and considerable interindividual heterogeneity. Although knowledge of the genetics and biochemistry of the disorders has recently improved, little is known of the pathological processes that actually result in end-organ damage. This may result in cytokine secretion, cellular proliferation, disturbed calcium homeostasis, exaggerated inflammation and perturbed control of apoptosis. In Gaucher disease, where storage cells are macrophages that play an essential role in host physiology and pathogenesis of inflammatory and immunological responses, a wide variety of enzymes, cytokines and coagulation factors are perturbed (Table 15. Prevalence Recent studies suggest that the true prevalence of lysosomal storage disorders may be higher than previously thought. This is because patients with minimal symptoms, such as homozygotes for the Gaucher N370S mutation, may not come to medical attention and also because of misdiagnosis of multisystem disorders such as Fabry disease. Diagnosis In the absence of an informative family history, diagnosis of lysosomal storage disorders requires a high degree of clinical suspicion. These may have been requested incidentally, for example the finding of Gaucher disease in the bone marrow biopsy of a thrombocytopenic patient or Fabry disease in a renal biopsy, or may be a specific directed examination such as a skin biopsy in a patient with the characteristic rash of Fabry disease. Levels of lysosomal enzymes may be measured in plasma or leucocytes using commercially available synthetic or naturally occurring labelled substrates. Once a candidate enzyme is identified, analysis of the corresponding gene may identify a specific mutation and facilitate rapid screening of other family members. As effective treatment becomes available for a larger number of disorders, it is increasingly important that patients should be diagnosed as early as possible as presymptomatic individuals may be candidates for early intervention. Tissue General aspects of therapy Effective treatment of lysosomal storage disorders self-evidently involves reduction of the stored compound and prevention of its re-accumulation. The resulting translated proteins are chemically modified, purified and prepared for infusion. Antibodies readily develop to infused enzyme and this certainly attenuates effectiveness in some diseases. Analogues of small molecules are used to inhibit the activity of synthetic enzymes. Thus, glucose and ceramide analogues can be used separately to reduce the activity of the enzyme glucosylceramide synthetase. This approach is only feasible in individuals with later-onset forms of the diseases who harbour mutations associated with detectable levels of residual enzyme activity. Some mutations lead to reduced levels of residual enzyme activity by causing misfolding of peptide chains or abnormal intracellular transport. The oral administration of small molecules (pharmacological chaperones) that can rescue misfolded or unstable enzymes is currently under active investigation for several lysosomal storage disorders. Such chaperones are designed to bind specifically to mutant peptides, aid their passage through the endoplasmic reticulum, rescue them from proteosomal degradation and guide them to the lysosome. Prognosis the clinical course of infants diagnosed with a lysosomal storage disorder usually follows a predictable path of loss of learned skills and neurological deterioration until death results from infection and progressive organ damage. When onset is later, in adolescents and adults, the clinical course is more varied and the prognosis depends on the major organ systems affected. However, patient heterogeneity is such that it is not possible to predict which patients are most likely to experience significant morbidity or early mortality. Clinical manifestations In view of recent advances in therapy, Gaucher disease, Fabry disease and Pompe disease are presented in greater detail below. Gaucher disease Gaucher disease is due to deficiency of the enzyme glucocerebrosidase, a lysosomal enzyme that hydrolyses glucosylceramide to glucose and ceramide (Figure 15. Affected individuals have a mutant enzyme with reduced activity, resulting in accumulation of the substrate (glucosylceramide) in lysosomes of reticuloendothelial cells. It is one of the commonest lysosomal storage disorders, with an estimated incidence of 1 in 60,000 to 1 in 80,000 individuals. Clinical features Clinical manifestations are due to cellular and tissue damage consequent upon accumulation of sphingolipid-laden macrophages in reticuloendothelial organs. This is the acute neuronopathic form of the disease, which presents with neurological complications in early infancy and usually leads to death before the age of 2 years. Type I Gaucher disease is a heterogeneous disorder that may present in childhood or in late adult life. Symptomatic individuals have hepatosplenomegaly, skeletal disease and bone marrow infiltration, leading to pancytopenia. Rarer manifestations of type I Gaucher disease include pulmonary disease, skin involvement and peripheral neuropathy. Patients with type I Gaucher disease have an increased incidence of malignancy generally and an increased incidence of haematological malignancies, especially B-lymphocyte disorders (myeloma, monoclonal gammopathy of undetermined significance) and myelodysplasia.
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Since many new treatments will be available hypertension categories cheap 2 mg aceon with amex, novel approaches to clinical trial design will need to develop to make more rapid progress hypertension medication drugs purchase aceon paypal. Much greater international collaboration is needed to provide sufficient numbers of the patient subgroups arrhythmia lying down generic aceon 4 mg without prescription, or different statistical methods will be required arrhythmia multiforme order aceon line. Cancer Genome Atlas Research Network (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. Occasionally patients will present with primary involvement of nodal or extranodal sites, with minimal evidence of bone marrow involvement. Most patients present with a combination of symptoms resulting from bone marrow failure, including fatigue and weakness due to anaemia, haemorrhagic complications of thrombocytopenia and/or signs and symptoms of recurrent infection due to neutropenia. Approximately 10% of patients will have obvious signs of organ involvement at diagnosis with splenomegaly, liver impairment, lymphadenopathy, testicular swelling or meningeal syndrome with neurological symptoms. Patients with T-cell disease may have large mediastinal masses and can present with features of superior vena cava obstruction. Examination of a blood film reveals circulating lymphoblasts in over 90% of cases. It is commoner to see very high white cell counts in T-cell disease rather than B-cell disease. Most adults will be anaemic at diagnosis, although severe anaemia < 80 g/L is unusual. The bone marrow will be hypercellular with a marked infiltration of leukaemic blasts, which amount to over 25% of total nucleated cells. In some cases the marrow may be difficult to aspirate due to increased reticulin and a trephine biopsy should be performed. Blastic transformation of chronic myeloid leukaemia should be ruled out by morphologic examination where possible (presence of basophilia, prominent granulocyte component and dwarf megakaryocytes in the bone marrow). B-cell disease is then further subclassified, based on the presence of recurrent cytogenetic abnormalities that are known to have prognostic value clinically (Table 21. These subtypes are defined according to their stage of differentiation, although aberrant or asynchronous antigen expression is common. The blast cells are negative for TdT and express surface antigens of mature B cells, including surface membrane immunoglobulin. Aberrant expression of myeloid antigens is not uncommon and should not detract from the correct diagnosis. Since this subtype is associated with a better prognosis, its identification is of particular importance. However, when good-risk aberrations are detected at diagnosis in adults they carry the same prognostic value as they do in children. New cytogenetic groups are continuing to be defined in both B-cell and T-cell disease, although their clinical relevance needs to be explored within the context of large clinical trials. It is now possible to quantitate treatment response very accurately and reproducibly, to the level of 1 leukaemic cell in 10,000 using various methods, as shown in Table 21. The most standardized method identifies patient-specific immunoglobulin heavy chain and T-cell receptor gene rearrangements, which Table 21. However, the clinical potential of treatment prior to haematological relapse is not yet clear. A predictive factor is a clinical or genetic characteristic that provides information on the likely benefit from treatment. Consequently, prognostic factors define the effects of pre-existing patient or leukaemia characteristics on outcome, whereas predictive factors are used to define the effect of treatment. Response to initial therapy, early steroid response and quantification of minimal residual disease at protocol-defined time points are validated predictive factors. There is no universally accepted algorithm by which risk status is measured in all cases. Hence, how we vary our therapeutic strategy in response to prognostic and predictive factors will change as studies identify new markers and define their inter-relationships. The commonest symptoms that cause the patient to seek medical advice are recurrent infection or petechiae or other haemorrhagic problems. Approximately half of all patients will have findings of lymphadenopathy, splenomegaly and/or hepatomegaly at presentation. According to data from two large German trials, 14% of patients will have a mediastinal mass at presentation and the majority of these (85%) will subsequently be shown to have T-cell disease. Almost any organ can be infiltrated by leukaemic blasts at diagnosis and approximately 10% of patients will have demonstrable involvement clinically. Pleural effusions are most common and tend to occur in association with mediastinal masses in T-cell disease. Bone pain at presentation is rare in adults compared to children, with bone lesions being demonstrated in 1% of adult patients. Leukaemic infiltration of other organs such as lung, kidney and skin is rarely observed and tends to be associated with poorer outcomes. Patients should be asked specifically about the presence of symptoms of sinusitis and haemoptysis. Investigations at diagnosis must include a full blood count, blood film examination and bone marrow (see also Chapters 19 and 20).