Hematologic Malignancies: Myeloproliferative Disorders - part 9 potx

symptom complex that should suggest the presence of PV or its companion myeloproliferative disorder, ET. In an era of improved access to medical care, it is important to remember that PV patients are being recognized much earlier in the course of the disease, often when they are still asymptomatic. 16.5.2 Signs What is true for symptoms is also true for the signs of PV, which is now frequently recognized when a routine complete blood count is obtained in an asymptomatic patient. Unfortunately, as shown in Table 16.6, more often than not simultaneous elevation of the red cell, white cell, and platelet counts is not found. Of course, as observed by Osler and endorsed by the PVSG, some patients can present with erythrocytosis and splenomegaly alone (Osler 1903). Because of a propensity to hemorrhage, particularly in the gastrointestinal tract, PV patients can present w ith a microcytosis. Microcytic erythrocytosis is an important diagnostic clue but can be seen w ith other forms of erythrocytosis and in thalasse- mia trait; in the latter situation in the absence of iron deficiency, however, the red cell distribution width (RDW) will be normal (Bessman 1977). PV is a hyper- coagulable state and thus, the disorder needs to be considered with any unexplained episode of thrombosis, and particularly intra-abdominal venous thrombosis, since PV is the commonest cause of hepatic vein thrombosis in the Western hemisphere (Parker 1959). In young women, hepatic vein thrombosis is a frequent presenting manifestation (Valla et al. 1985). Plethora, particularly of the face, conjunctiva, mu- cous membranes, and hands can be striking and hypertension is another sign of the expanded red cell mass. Easy bruising, epistaxis, or g ingival bleeding occur as a consequence of circulatory stasis, or of acquired type IIa von Willebrand’s disease, if the platelet count is in excess of 1,000,000/ll. Splenomegaly is the most common physical finding other than plethora and is usually modest in extent. Hepatomegaly is much less common and, with the exception of hepatic vein thrombosis, is not seen in the absence of splenomegaly. Gout or renal stonesarerarely presenting manifestations of the disease. 16.6 The Consequences of PV The consequences of PV are listed in Table 16.7. Given the increasing burden of hematopoietic progenitor cells and their progeny, the complications of PV are diverse and usually the result of cell accumulation, cellular metabolism, or cellular transformation. Thrombotic and hemorrhagic events are the most common and frequent severe complications of PV. His- torically, thrombosis was the presenting feature in PV in up to 49% of patients, while there was a 40% incidence of thrombosis during the course of the illness (Spivak 2002). Not surprisingly, thrombotic events tended to re- occur in patients who previously had a thrombotic event. Importantly, several studies have emphasized a high frequency of vascular accidents in patients several years before the diagnosis of PV was first made (Anger 286 Chapter 16 · Polycythemia Vera – Clinical Aspects Table 16.6. Laboratory abnormalities in PV (From Spi- vak JL. Myeloproliferative disorders. In: Handin RI, ed. Blood. Philadelphia: Lippincott Williams & Wilkins, 2003, with permission) Percentage (%) Range Erythrocytosis 91 88–99 Leukocytosis 67 43–84 Thrombocytosis 52 40–63 Reticulocytosis 35 6–54 Elevated Leukocyte Alkaline Phosphatase 81 63–100 Table 16.7. The consequences of polycythemia vera Consequence Cause Thrombosis, hemorrhage, hypertension Elevated red cell mass, decreased vWF multimers Organomegaly Extramedullary hematopoiesis or elevated red cell mass Pruritis, acid-peptic disease Inflammatory mediators Erythromelalgia Thrombocytosis Hyperuricemia, gout, renal stones Increased cell turnover Myelofibrosis Reaction to the neoplastic clone Acute leukemia Therapy-induced or clonal evolution et al. 1989; Gruppo Italiano Studio Policitemia 1995). Thrombosis also accounted for up to 40% of deaths. Ar- terial thrombosis was more common than venous thrombosis with myocardial infarction and stroke b eing the most frequent events. Remarkably, although PV is the commonest cause of intra-abdominal venous thrombosis (Najean et al. 1987; Parker 1959), peripheral venous thrombosis was the commonest site for venous thrombosis in several large series (Gruppo Italiano Stu- dio Policitemia 1995; Landolfi et al. 2004). The incidence of hemorrhage is less common than thrombosis, occurring in approximately 20% of patients and involving the gastrointestinal tract or the central nervous system. However, it is fatal in less than 10% of patients (Wehmeier et al. 1991). Bleeding in PV has two major mechanisms: vascular stasis with endothelial cell damage due to hyperviscosity, and the development of acquired type IIa von Willebrand disease. The contri- bution of an elevated red cell mass to a hemorrhagic diathesis is well illustrated in mice genetically engi- neered to overproduce erythrocytes, in whom death occurred as a consequence of disseminated hemorrhage (Shibata et al. 2003). It is of further interest to note that many of the patients initially described as having “hemorrhagic thrombocytosis” actually had PV (Ozer et al. 1960). This is a reflection of the role of the platelets in contributing to the hemorrhagic diathesis of PV. As the platelet count increases, the concentration of high molecular weight von Willebrand multimers decreases (Budde et al. 1993), presumably due to platelet binding and proteolysis (van Genderen et al. 1996). Systolic hypertension is another feature of red cell mass expansion in PV but a feature that is more common to early descriptions of the disease when patients presented later in the course of the disease (Fig. 16.6). Initially, in PV, as the red cell mass increases, the plasma volume also increases, in contrast to secondary forms of erythrocytosis where there is plasma volume contrac- tion in an attempt to maintain a normal blo od volume. With expansion of the blood volume, there is initially a reduction in peripheral vascular resistance but even- tually, with continued distent ion of the vascular system, hypertension ensues. Platelet activation in PV causes a variety of occlusive or vasospastic syndromes including erythromelalgia, transient ischemic attacks, and ocular migraine. The frequency of these complications varies and in one recent large series in which many patients were pretreated to lower the leukocyte and platelet counts and their activation, erythromelalgia occurred in only 5% (Landolfi et al. 2004). Erythromelalgia is a peculiar syndrome characterized by erythema, warmth, and burning p ain primarily in the feet but also in the hands that is aggra- vated by heat, positional dependency, and exercise and relieved by elevation or cooling of the affected extrem- ities (Kurzrock and Cohen 1989). Erythromelalgia can be idiopathic, or due to conditions affecting the peripheral vessels or their enervation. However, it is most often seen in the chronic myeloproliferative diseases, PV and ET (Kalgaard et al. 1997), where it is caused by platelet aggregation and platelet-endothelial cell interac- tions that result in swelling and occlusion of arterioles that can be transient or permanent (Michiels 1997), with acrocyanosis and ulceration or necrosis of affected di- gits with preservation of peripheral pulses. Ocular migraine, which is characterized by scintillating scotoma- ta, dizziness, headache, transient ischemic attacks, and cortical blindness, is essentially the central nervous system equivalent of erythromelalgia. Importantly, these syndromes, while alarming, rarely leave permanent se- quelae. The etiology undoubtedly involves both platelet number and platelet activation since a reduction in either alleviates symptoms and aborts the syndrome. The role of platelet activation is implicated by the increase in urinary excretion of the platelet arachidonic acid metabolite thromboxane B 2 , associated with symptoms, histologic evidence of arteriolar thrombi, and aborting of the attack by cyclo-oxygenase inhibitors such as aspirin or indomethacin or reducing platelet number (Michiels et al. 1985). Indeed, al leviation of a 16.6 · The Consequences of PV 287 Fig. 16.6. Portrait of a PV patient of William Osler, circa 1915. The plethora and engorgement of blood vessels are evident in this gentleman with an expanded red cell mass and systolic hypertension symptoms with a single aspirin tablet is pathognomonic for erythromelalg ia. Acid-peptic disease is claimed to occur with a g reat- er frequency in PV than in the general population but the observations upon which this claim is based are primarily from older studies. A specific blood group relationship was not observed (Perkins et al. 1964) and the role if any of H. pylori is unknown, as is the role of pro- miscuous histamine (Westin et al. 1975) or cytokine release (Gilbert et al. 1966). A relationship to circulatory stasis and vasoconstriction due to nitric oxide scaven- ging by hemoglobin also need to be considered when the red cell mass has not been controlled (Huang et al. 2005). Hyperuricemia in PV is due to the excessive turnover of blood cells, not altered urate metab olism (Yu et al. 1956), but the development of secondary gout or uric acid stones are uncommon in the absence of cy- toreductive therapy. Pruritus, usually aquagenic in nature and, like erythromelalgia, a not infrequent presenting manifestation of PV whose diagnostic significance is commonly over- looked initially, occurs in about 30% of patients. For some, the pruritus is a minor annoyance but for other patients it is an exquisite form of pain that prevents them from conducting their normal activities. The mechanism for pruritus in PV has been a matter of debate. Evidence for (Jackson et al. 1987) and against (Bu- chanan et al. 1994) a role for increased cutaneous mast cell activity has b een obtained and roles for histamine (Westin et al. 1975), iron deficiency (Salem et al. 1982), and platelets have been proposed. Vascular stasis is undoubtedly involved since phlebotomy alleviates the pruritus in some patients. Indeed, it appears safe to say that the mechanisms for pruritus in PV are probably multiple, but why not all patients are affected is unknown. Organomegaly, with its attendant mechanical problems including portal hypertension, is due initially to engorgement of the spleen with blood in untreated patients but with time, in some patients more than others, the enlargement of the spleen and liver is due to extramedullary hematopoiesis as discussed above. In addition to its space-occupying effects, splenic enlargement leads to an increase in splanchnic blood flow to a degree that portal hypertension ensues (Rosenbaum et al. 1966) and in some patients esophageal varices develop, often complicated by hemorrhage. Thrombosis of the hepatic vein can also lead to portal hypertension, and splenic vein thrombosis can lead to gastric varices. Hepatome- galy is common with hepatic vein thrombosis and also after splenectomy as the liver becomes a major site of extramedullary hematopoiesis (Towell and Levine 1987). As discussed above, much has been written about the development of myelofibrosis in PV and the spent or postpolycythemic myeloid metaplasia phase of the disease. Myelofibrosis, of course, is a reactive process and poses no impediment to marrow cell function. Mye- loid metaplasia also do es not represent a failure of bone marrow function either, since there is no correlation between its presence and bone marrow failure. Confusion has arisen with respect to these processes, because a dis- tinction was never made between the bone marrow failure state caused by the use of alkylating agents and the natural course of PV. Bone marrow failure is an expected consequence of the use of alkylating agents, while the frequency with which bone marrow failure occurs in PV in their absence is still unknown. 16.7 The Management of PV 16.7.1 A Strategy for the Treatment of PV Any discussion of the treatment of PV must first ac- knowledge some disturbing shortcomings with respect to our knowledge about this disorder. First, since a specific clonal marker for the disease is lacking, we do not know whether what has been clinically defined as PV represents a single disease or a group of related disorders. Indeed, given variable natural history of PV and the epidemiology of the JAK2 V617F mutation, the latter is a likely possibility. Second, prior to the discovery of JAK2 V617F and lacking a specific clonal marker, it was not possible to decide wh ether a particular therapy was curative or merely palliative. Third, while the natural histor y of PV is not completely defined, there is good evidence that disease tempo varies. Unfortunately, no laboratory markers have been identified that permit risk stratification with respect to this or the known complications of the disorder. Fourth, current concepts of the treatment of PV are based on flawed natural history studies and clinical trials in which there was treatment bias based on a total misunderstanding of the pathophysiology of the disease. Fifth, PV is now being discov- ered earlier in its course than was the case previously, but no attempt has yet been made to redefine treatment goals in light of this. Finally, with respect to this latter situation, cur rent estimates of longevity in PV are based 288 Chapter 16 · Polycythemia Vera – Clinical Aspects on studies of patient populations diagnosed years ago and treated with drug regimens that are no longer considered safe (Gruppo Italiano Studio Policitemia 1995; Passamonti et al. 2004). 16.7.2 Phlebotomy As discussed earlier, expansion of the red cell mass in PV, in contrast to other forms of erythrocytosis, is associated with either no change or an increase in the plasma volume (Table 16.3). This results initially in a fall in blood vessel dilatation and a decline in peripheral vascular resistance, but with time peripheral vascular resistance increases as bloo d vessels are distended to the extent possible. This was probably best described by We- ber in 1908, who noted, “In every case examined after death the distention of the visceral vessels has been very striking, the mesenteric vessels presenting sometimes the appearance of having been forcibly injected for pur- poses of anatomical dissection” (Weber 1908). There are several important issues involved here. First, the hematocrit is the principle determinant of blood viscosity but as discussed above, it is not possible to estimate the extent of red cell mass expansion from the peripheral blood hematocrit. Second, blood viscosity is an expo- nential function of the hematocrit, and red cell aggregation also increases as the hematocrit rises (Wells and Merril l 1962). In addition to vessel wall distention and endothelial cell injury, the increased number of red cells forces leukoc ytes and platelets against the vascular en- dothelium and against each other, where cell-cell inter- actions can lead to activation of coagulation. Phlebotomy is a global antidote for these problems (Table 16.7) and also relieves the symptomatology associated with impaired cerebral blood flow (Thomas et al. 1977). The initial red cell mass determination permits an assessment of the amount of blood that needs to be removed, and target hematocrits of <45% in men and <42% in woman should be the goal. Current data suggests that the rate of thrombosis is negligible at these gender-specific hematocrits (Pearson and Weatherly- Mein 1978) and cerebral blood flow is normalized. This approach will alleviate the symptoms of headache, confusion, tinnitus, dizziness, and epistaxis and sometimes even alleviate itching. Phlebotomy also quickly im- proves blood viscosity by expanding the plasma volume. Contrary to common intuition, phlebotomy does not provoke thrombocytosis (Messinezy et al. 1985). Although most patients tolerate rapid lowering of the red cell mass, in some elderly patients there may be va- somotor instability initially (Kiraly et al. 1976); in this situation, removal of smaller amounts of blood (250 ml) and replacement with crystalloid is prudent. Phle- botomy also has the useful effect of restoring balance to the coagulation system and restoring platelet function to normal (Wehmeier et al. 1990). The goal of phleb otomy is twofold: first, to restore the red cell mass to normal to prevent thrombosis or hemorrhage and to allev iate symptoms and second, to develop a state of iron deficiency to prevent a rapid re- currence of red cell mass expansion. Iron absorption is maximal in PV (Finch et al. 1950), and once a state of iron deficiency is created, it will take approximately 3 months for iron balance to be restored and for phlebotomy to become necessary again. Not only will the inter- val for phlebotomy be increased but its frequency will also decline unless an additional source of iron is intro- duced. Iron deficiency in the adult in the absence of anemia does not impair aerobic performance (Rector et al. 1982) but may induce pica, usually in the form of ice craving (pagophagia). It is also worth emphasiz- ing the benefits of phlebotomy are immediate, while at- tempts to lower the red cell mass with chemotherapy not only take time, they are also often unsuccessful (Gruppo Italiano Studio Policitemia 1995; Najean and Rain 1997). 16.7.3 Management of Leukocytosis and Thrombocytosis Leukocytosis is rarely extreme in PV but patients may become symptomatic if the leukocyte count exceeds 50,000/ll, possibly from either cytokine release or small vessel stasis of immature leukocytes in the lungs or else- where. Leukocytosis may also be associated with hyperuricemia and this will require therapy if the uric acid exceeds 10 mg% or when chemotherapy is contem- plated. Asymptomatic thrombocytosis in PV ordinarily re- quires no treatment. Exceptions to this rule would be patients with conditions predisposing to thrombosis such as coronary artery disease, peripheral vascular disease, diabetes mellitus, hypertension, tobacco abuse, or a history of prior thrombosis. In a number of studies, myeloproliferative disease patients over age 65 also ap- peared to be more vulnerable to thrombosis than their a 16.7 · The Management of PV 289 younger counterparts without cardiovascular risk factors (Barbui and Finazzi 1997; Cortelazzo et al. 1995). Erythromelalgia or ocular migraines do dictate treatment to inhibit platelet function or reduce platelet number. Aspirin (or ibuprofen) is the simplest and quickest treatment for erythromelalgia, but the remedy is temporary and not always completely effective. Both aspirin and ibuprofen can also promote bleeding and are contraindicated when the platelet count is sufficiently high to cause a reduction in von Willebrand multimers and a prolongation of the ristocetin cofactor assay. This usually occurs when the platelet count exceeds 1,000,000/ll. In this instance, a reduction in platelet number will be necessary to control symptoms. There are three choices of therapy for thrombocytosis when either aspirin or ibuprofen is not sufficient: hydroxyurea, interferon alpha, or the imidazolequinazo- line derivative, anagrelide. Hydroxyurea has been the drug of choice because it is easy to administer, has a low incidence of side effects, and was shown to be supe- rior to aspirin in controlling microvascular thrombosis in ET (Cortelazzo et al. 1995). The recent ECLAP study also suggested that hydroxyurea was not leukemogenic (Landolfi et al. 2003). However, that study, like others before it, lacked a sufficient duration of observation to solidify this contention. It also needs to be emphasized that all major studies of the treatment of thrombocytosis have been conducted in ET and the extent to which the results can be extrapolated to PV is unknown. Therefore, the choice of therapy in this instance should be based on a physician-patient dialogue concerning the pros and cons of the available treatment options. It is the authors’ preference to use anagrelide or interferon alpha in younger patients while reserving hydroxyurea therapy for patient’s intolerant to these agents or with known cardiovascular risk factors. The extent to which the platelet count should be reduced is also a matter of debate. Anecdotal studies re- plete w ith reportorial bias suggest that the platelet count should be normalized (Regev et al. 1997), despite the fact that the platelets themselves will not be functionally normal, nor is there any data to suggest that a normal platelet count would be protective. Tailoring treatment to the individual patient appears logical. Thus, when there are cardiovascular risk factors or a prior history of thrombosis, lowering the platelet count to 500,000/ l or less would be prudent; when no such risk factors ex- ist, lowering the platelet count to achieve alleviation of symptoms or correction of a coagulopathy should be sufficient. Plateletpheresis has a very limited role in the management of thrombocytosis because it is not only inefficient when the platelet count is very high but its effect is also transient. Additionally, combination therapy such as aspirin and interferon alpha or aspirin and hydroxyurea may be useful but there is an increased risk of bleeding when aspirin is coupled with anagrelide (Harrison et al. 2005). Finally, since interferon alpha is not mutagenic and hydroxyurea appears to be, it seems more prudent to use hydroxyurea intermittently when- ever possible. 16.7.4 Pruritus Pruritus, usually aquagenic in or ig in, afflicts approximately 30% of PV patients. The symptoms may be mild and transient but in some patients the itching, stinging, or burning sensation provoked by water contact or even a humid environment can be unbearable. Since the mechanism is unknown, treatment has been empirical. In some patients, phlebotomy brings relief; in others a change in bathing habits or the use of a long-acting antihistamine is effective, but determining which one is often a matter of trial and error. Success has been claimed for serotonin antagonists (Wasserman 1976), antidepressants (Diehn and Tefferi 2001), danazol (Ko- lodny 1996), and iron repletion (Salem et al. 1982) but these claims are all anecdotal. Psoralen and ultraviolet A li ght therapy is an effective, if inconvenient and temporary remedy, but has its own toxicities such as skin hyperpigmentation and burns (Morison and Nesbitt 1993); ultraviolet B has its proponents as well (Baldo et al. 2002). Interferon alpha has a success rate of approximately 60% (Finelli et al. 1993) and a response can be seen in several weeks. Leukocyte reduc tion with hydroxyurea is also effective. 16.7.5 Extramedullary Hematopoiesis Control of extramedullary hematopoiesis in PV and, in particular, the splenomegaly that is its most common and prominent manifestation is the most difficult therapeutic challenge in this disorder. Initially, splenomegaly may respond to phlebotomy therapy but as the disease progresses, splenic enlargement is due to hematopoietic progenitor cell proliferation. There are currently four approaches for controlling splenomegaly due to ex- 290 Chapter 16 · Polycythemia Vera – Clinical Aspects tramedullary hematopoiesis: chemotherapy, radiother- apy, biologic response modifiers, and splenectomy. Al- kylating agents such as busulphan were once the main- stay of therapy for this purpose in PV. However, these agents are not only leukemogenic but also can cause severe cytopenias and chronic bone marrow failure. Hy- droxyurea is modestly effective in controlling splenomegaly but is leukemogenic when given in combination with an alkylating agent or even after one. Imatinib mesylate has also been used successfully to control splenomegaly in PV (Jones and Dickinson 2003; Silver 2003), but the response rate varies and the reasons for this are unknown. Splenic irradiation can be an effective temporizing remedy but has the r isk of depressing bone marrow function because the effective dose is not pre- dictable (Elliott et al. 1998). Furthermore, the adhesions that develop can make subsequent splenectomy difficult and hazardous. The reduction in spleen size is also temporary, although the treatment can be repeated successfully. Interferon alpha can reduce spleen size in approximately 60% of patients and while the effect is temporary if the interferon is discontinued, it can be reinstituted as needed (Lengfelder et al. 2000; Silver 1997). Thalido- mide is another biologic response modifier that has been used successfully to reduce splenomegaly in patients with idiopathic myelofibrosis (Mesa et al. 2003). Whether it is effective in PV is not know n. Splenectomy, while providing a definitive solution to the problem, has the disadvantages of the obligate mor- bidity and mortality associated with any major abdominal surgery, in addition to the particular risks in re- moving a massive spleen, the most important of which are hemorrhage and thrombosis. The risk of hemorrhage is increased if the red cell mass is not controlled, if there is extreme thrombocytosis with the development of acquired von Willebrand disease, and if there are significant adhesions due to splenic infarction or prior irradiation. Splenic, mesenteric, or portal vein thrombosis occurs in approximately 6–7% of patients postsplenectomy and is not correlated with the degree of thrombocytosis (Broe et al. 1981). Generally, this complication occurs within a month of surgery, and may be asymptomatic and difficult to detect by ultra- sound in the immediate postoperative period (Chaffan- jon et al. 1998). It is imperative that the patient’s nutr i- tional status be satisfactory before surgery and this may require parenteral hyperalimentation. Evaluation for portal hypertension should also be performed before surgery since splenectomy alone will not resolve this problem if varices are present. Postsple- nectomy, hepatic enlargement is not uncommon and has been observed occasionally to be fulminant with a fatal outcome (Towell and Levine 1987). Control of hepatomegaly in this situation can be difficult and there is not adequate experience with any remedy for guidance; irradiation is a temporary and toxic approach while 2- chlorodeoxyadenosine has been effective at the risk of severe myelosuppression (Tefferi et al. 1997). Low dose cyclophosphamide has also been anecdotally effective. Postsplenectomy leukocytosis and thrombocytosis are expected complications that may require chemotherapy (Schilling 1980). 16.7.6 Hepatic Vein Thrombosis Hepatic vein thrombosis is an uncommon but frequently catastrophic manifestation of PV. Since PV is the commonest cause of hepatic vein thrombosis, this diagnosis always needs to be considered when hepatic vein thrombosis is encountered, even if the hematocrit is normal, since this may be due to an expanded plasma volume (Lamy et al. 1997). Hepatic vein thrombosis is a medical emergency that needs to be recog nized promptly to relieve liver congestion and reduce portal venous pressure. If the thromb osis is acute, thromboly- tic therapy, which may require a supplemental supply of plasminogen in the form of fresh frozen plasma, may be effective. Otherwise, anticoagulation, stenting, or a transjugular intrahepatic portosystemic shunt (TIPS) procedure should be instituted promptly together with hematocrit reduction if it is elevated or even normal. 16.7.7 Pregnancy Pregnancy is not an uncommon issue in PV given that among patients below the age of 40, PV is predominant- ly a disease of women. Unfortunately, published experience is limited (Ferguson et al. 1983) and this, coupled with lack of understanding of the pathophysiology of PV, has led many physicians to advise against concep- tion for these patients. However, the major risks of PVare not different in pregnancy than they are in its absence and the most important of these is thrombosis. The particular risk in this regard in pregnancy is the expansion of the plasma volume that normally accompa- nies this condition. Plasma volume expansion only a 16.7 · The Management of PV 291 further serves to mask the expanded red cell mass of PV and creates a false appearance of normalcy. Stated dif- ferently, a normal hematocrit in a pregnant PV patient is evidence for an expanded red cell mass and an invita- tion for placental insufficiency or a thrombotic event. Therefore, PV patients who wish to become pregnant should have their hematocrit maintained no higher than 36% and once pregnant, the hematocrit should not be allowed to rise above 33%. There should be no concern in this regard with respect to the fetal iron supply but folic acid supplementation is mandatory. It is expected that a high platelet count will fall during pregnancy (Turhan et al. 1988) and von Willebrand factor will rise physiologically. Splenomegaly can b e controlled before pregnancy or safely during it with interferon alpha; hydroxyurea and anagrelide are contraindicated. 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