Common and emerging infectious causes of hematological malignancies in the young

APMIS 106: 585-597. 1998 Printed in Denmark . All rights reserved

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Common and emerging infectious causes of hematologiccd malignancies in the young

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TUULA LEHTINEN and MATT1 LEHTINEN

Department of Clinical Oncology and School of Public Health, University of Tampere and Department of Infectious Disease Epidemiology, National Public Health Institute,

Helsinki, Finland

Lehtinen, T. & Lehtinen, M. Common and emerging infectious causes of hematological malignancies in the young. APMIS 106: 585-597, 1998.

Comparative epidemiological studies have for a long time suggested a link (or links) between infectious agents and hematological malignancies in the young. Identification of Epstein-Barr virus (EBV) as the major cause of specific subtypes of Burkitt’s lymphoma and Hodgkin’s disease 20 and 10 years ago, respectively, and the recent involvement of human T-cell leukemia virus in non-Hodgkin’s lymphomas of the T-cell lineage in young adults in Jamaica have given further credit to early presump- tions that these diseases have an infectious etiology. The spectrum of possibly involved viruses: old, EBV, and new, herpesviruses 6, 7 and 8, and unknown retroviruses - as well as the list of partially or totally unresolved disease entities: Hodgkin’s disease in adolescents, non-Hodgkin’s lymphomas in the immunocompromised, and acute lymphocytic leukemia - is rapidly expanding. Both direct and in- direct transforming effects of the above-mentioned viruses are being rapidly disclosed. However, the complex interaction between the different viruses and other causes of hematological malignancies in the young guarantees that many things remain to be discovered also in the future.

Key words: Childhood; herpesvirus; leukemia; lymphoma; retrovirus.

Matti Lehtinen, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland.

Following the clinical, virological and epidemiological discoveries of Burkitt (1958), Epstein et al. (1964), MacMahon (1957), Ellermann & Bang (1 908-1 909) (cited from Shimkin 1980) and Hinuma et al. (1982), infections caused by two viruses (Epstein-Barr virus, EBV, and human T-cell leukemia virus, HTLV-I) have now been established as major causes of Burkitt’s lymphoma (BL), Hodgkin’s disease (HD), and adult T-cell leukemia (ATL) (de-The et al. 1978, 1985; Razzouk et al. 1996; Pallesen et al. 1993; Hollsberg & HaJer 1993). Apart from BL and HD, little is known about the etiology of hematological malignancies in the young, but infections, especially viral infections, have for four decades remained at the top of the list of poss-

ible causes (Stewart et al. 1958; MacMahon 1992; Liebowitz 1995). In the following, we will review current knowledge on the possible infectious etiology of acute lymphocytic leukemia (ALL), HD, and non-Hodgkin’s lymphoma (NHL) in the young.

COMPARATIVE EPIDEMIOLOGY OF HEMATOLOGICAL MALIGNANCIES IN

THE YOUNG

Geographical and ethnic comparisons Childhood leukemia and ALL peak between

0 4 years, and are almost equally common worldwide with age-standardized incidence

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rates varying at around 40 and 30 cases/million, respectively (Parkin et al. 1988). Recent studies have shown that the earlier reported low incidence rates, of for instance India, were due to underregistration, and that is still the case for girls (Draper et al. 1994; Nandakumar et al. 1996; George 1997). Furthermore, except for US blacks who have a low incidence of ALL, studies on immigrants have not reported any major ethnic differences with regard to ALL incidence (Bowman 1984; Goodman et al. 1989).

NHLs other than BL show no consistent geographical patterns (Stiller & Parkin 1990). Be- fore the AIDS era the highest incidence rates of up to 80 per million children for BL were seen in equatorial Africa and Papua New Guinea. High to moderate rates are also found around the Mediterranean area and in South America, whereas most of the western countries have a low incidence with less than 2 per million (Par- kin et al. 1988; Sandlund et al. 1997). It is important to note that the incidence of BL peaks in the highly endemic areas and in northern Africa between 5-9 years, whereas a predominance of cases in 0-4 year olds is seen in West Asia (Stiller & Parkin 1990). The African - Asian/South American difference also holds true for clinical presentation (head and neck vs abdominal) of BL (Stiller & Parkin 1990; Sand- lund et al. 1997). Unfortunately, data on ethnic differences in BL, e.g. among Indian immigrants in equatorial Africa, are lacking.

The geographical distribution of H D incidence is not quite the opposite of that of BL, but the scarce data available suggest that H D is rare in areas endemic for BL (Stiller & Parkin 1990). The highest incidence of childhood H D is seen in West Asia and Central and South America (10.8-8.6 per million), whereas the Nordic and Far East Asian countries are moderate and low incidence areas (4.0-2.5 and 2.1- 0.7 per million, respectively) (Parkin et al. 1988). As pointed out already in the 1970s H D incidence in the developing countries peaks between ages 5-9 years, which results in relatively low H D incidence in adolescents and adults (Correa & O’Connor 1971; Stiller & Parkin 1990; Hartge et al. 1994). This is in line with observations of a high incidence of childhood H D among US whites in warm climates, but high incidence/mortality among corresponding adolescents in cold climates (MacMuhon 1966;

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Stiller & Parkin 1990). The dichotomy, however, does not seem to apply to the US Hispanic population, which shows a relatively high incidence of both childhood and adolescent H D (Spitz et al. 1986; Parkin et al. 1988; Hartge el al. 1994).

Incidence trends Due to the more or less artificial division of

children and adolescents at the age of 15, and well-known differences in registration practices (Draper et al. 1994) systematic comparisons of trends in national incidence rates of hematological malignancies in children (0-14 years), adolescents and young adults ( 1 5-25 years) are rare and international comparisons do not exist. For some malignancies, such as HD, division at the age of 15 nowadays splits the first incidence peak into two, and considering the rapid decline of age of pubescence this has to a great extent jeopardized long-term surveillance of incidence trends of a number of hematological malignancies.

In the Nordic countries no increasing trends for total childhood leukemia were found between the 1940s and 1980s or between the 1980s and 1990s (Darby et al. 1992; NOPHO 1997). For acute lymphocytic leukemia (ALL), which comprises 80 to 90% of all childhood leukemia, a gradual increase of about 1%) per year has been documented in the UK and US (Con- necticut) since the 1950s and 1930s up to the 1990s and 1980s, respectively (Draper et ul. 1994; van Hoff et al. 1988). Studies starting in the early 1970s have found temporary increasing trends of ALL incidence in the Netherlands, USA, and in some parts of Australia (Cuehergtt et al. 1989; McCredie et al. 1992; Miller et al. 1993; Giles et al. 1995), but their impact remains open to debate.

Compared with leukemias, fewer incidence trend data are available on malignant lymphomas in the young. During the past 20 years the incidence of NHL in childhood has increased on average 1.5% per year in the US (Ries et al. 1994). This may in part be due to the spread of human immunodeficiency virus (HIV) in the US population, which is largely responsible for the doubling of NHL incidence rates in young adults. No increase of NHL in childhood has been documented in the Nordic countries during the 1980s and 1990s (NO-

CAUSES OF CHILDHOOD LEUKEMIAS A N D LYMPHOMAS

PHO 1997).The incidence of NHL in young adults has, however, been increasing for at least three decades in the US (Hartge et al. 1994) and immunocompromising factors other than HIV are probably involved (Sandlund et al. 1996).

With respect to HD in adolescents and young adults, a continuous shift towards younger ages, or in other words a sharpening of the incidence peak, has been taking place for five decades in the US (Connecticut) (Hartge et al. 1994). Al- though this close to 10-fold increase in HD incidence in adolescents may well be due to earlier exposure to a common causal agent, some indi- cation of an age-cohort effect, especially in fe- males born between 1950-1970, can also be found (van Hoff et al. 1988; Polednak 1994). Be- tween the 1970s and 1980s a more gradual increase, on average 1% per year has been found in other US and Australian studies on adolescent and childhood HD (Devesa et al. 1987; Hartge et al. 1994; Giles et al. 1995). Between the 1980s and 1990s no increase in the incidence of childhood and/or adolescent HD in the Nordic countries or UK has been noted, except in Finland where the median age of the first incidence peak has shifted from 25-30 years to 15-20 years (Cartwright et al. 1997; Finnish Cancer Registry 1995, 1996, 1997).

Space-time clustering Clustering of hematological malignancies in

the young was for a long time perhaps the most controversial chapter of the childhood leukemia and lymphoma literature. Although space-time clusters can arise from environmental exposures other than infectious agents, much of the controversy originally resulted from ignorance of this basic assumption (Gardner et al. 1990; Alexander 1993; Doll et al. 1994; Draper et al. 1997).

That childhood ALL clusters occur in relation to population mixing (Kinlen 1988; Kin- len et al. 1990) has recently been confirmed in comprehensive studies in Greece, Italy, the UK, and Hong Kong (Kinlen & Petridou 1995; Petridou et al. 1996; Gilman et al. 1997; Alex- ander et al. 1997). ALL clusters have not been found in the metropolitan regions of the US (Glass & Mantel 1969; Muirhead 1995), but this may be due to the fact that it is easier to detect clusters in rural populations (Alexand-

er & Boyle 1996). Delayed exposure to an infectious agent, which is suggested to be the critical event in leukemogenesis (Greaves 1988), is also more likely in rural populations, but the epidemiology of the underlying infectious agent(s) is likely to vary by country and continent. In any case, not only the association of ALL risk with population mixing (Kinlen 1988; Kinlen et al. 1990) and delayed exposure (Greaves 1988; MacMahon 1992) but also reported association of risk with increased population density ( M c Whirter & Ba- con 1980; Muirhead 1995) should fit specific geographical/epidemiological patterns of the suspected agent. The patterns could be tracked in archival population-based serum banks available in the Nordic countries, the US and the UK.

The extent to which the population mixing/ infectious agent theory is applicable to childhood NHL is not clear. Increased incidence of NHL has been found in many of the small clusters identified in the proximity of nuclear plants in the UK (Roman et al. 1993; Bithell et al. 1994; Draper et al. 1997). Unfortunately, comprehensive studies on NHL clusters in other countries are rare.

There is no evidence suggesting a link between clustering of HD and ALL (Gilman et al. 1997). Age and histological heterogeneity most- ly explains the controversial results on clustering of HD (Vienna et al. 1971; Alderson & Nayak 1971; Grufferman & Delzell 1984). Re- cent data on clustering of nodular sclerosing type HD among adolescents in the UK between 1984-1988 (Gilman et al. 1997), however, make it likely that new HD clusters will be identified in the future. The special features of HD, sea- sonal/temporal clustering (Grufferman & Delzell 1984; Gilman et al. 1997) should be considered in forthcoming studies.

New developments in international multi- centre studies and mathematical modelling (Alexander et al. 1996) suggest that ecological approaches will soon provide answers to the question what has happenedhs happening to the incidence of hematological malignancies in the young, and where and when have these changes occurred. It is, however, important to note that in the end identification of the causes requires longitudinal case-control and/or case-cohort studies. Results of such studies will also bring

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us closer to a final answer to the most important question: what about the future?

DISEASE AND/OR INFECTIOUS DISEASE SPECIFIC ASSOCIATIONS

In the following, we will first present the lessons learned from etiopathogenetic studies on BL, NHLs other than BL, and HD in the young in order to highlight what is already known about one of the causal agents, EBV, and susceptibility to its action and malignant sequelae. Thereafter, new infectious agents, diseases and disease associations are presented, and finally data on emerging infectious causes of ALL are considered.

EBV and B L In a prospective study of children under 8

years of age in Uganda, individuals with high antibody titres to EBV capsid antigens were found to be at highly increased risk of BL, and the risk increased with increasing levels of antibodies (de-The et al. 1978; Geser et al. 1982). 100% of these endemic BLs, 75-50% of Latin American BLs, but not more than 25% of sporadic BL tumours are EBV DNA-positive and express the EBV nuclear antigen-1 (EBNA1) and nuclear RNAs (EBER) of the type I latency of EBV (Gutierrez et al. 1992; Niedobitek et al. 1995; Sandlund et al. 1997).

The other pathognomonic feature of BL is the juxtaposition of the c-myc gene to one of the immunoglobulin receptor subunit genes on chromosome 2, 14 or 22 (Klein & Klein 1985). The dysregulated expression of c-myc results in increased complex formation between the myc protein and a DNA-binding max protein, which by transcriptional activation paves the way for progression of the cell cycle and lymphoproliferation (Sandlund et al. 1996; Henriksson & Luscher 1996).

In addition to the EBV positivity of BL, a similar geographical gradient exists in the distribution of the chromosome 8 breakpoints: far upstream of c-myc in endemic BL, immediate 5’ of c-myc in Latin American BL, and within the transcriptional unit in sporadic BL (Barriga et al. 1988; Gutierrez et al. 1992). This suggests at first glance a critical role for EBV in the first alternative. A comparable dichotomy in the clinical presentation (head and neck vs abdomi-

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nal) and immunophenotypes (CD21 vs CALLA) of the endemic BL and sporadic BL (Stiller & Parkin 1990; Magruth 1990) fits the picture of EBV infection and c-myc translocation being the two major successive steps in the genesis of endemic BL. Lack of correlation between the far upstream breakpoint of c-myc and EBV positivity of the Latin American BL cases, and conversely the recent discovery of disrupted EBV genomes in the sporadic BL cases previously thought to be EBV negative, however, complicate the picture (Gutierrez et al. 1992; Juin et al. 1994; Razzouk et al. 1996).

EBV and NHLs other than B L In the immunocompromised, the association

of EBV with benign and malignant lymphoproliferations manifesting as different high-grade NHLs or H D is well established (Alero-Thomas et al. 1990). In the immunocompetent the role of EBV is more or less restricted to peripheral T-cell lymphomas where different types of EBV latency, expression of EBERs, nuclear antigens also other than EBNA1, and LMPs take place (Pallesen et al. 1993). These malignancies have high-grade histopathological manifestations such as anaplastic large cell lymphoma, but occur very rarely in childhood (Pallesen et al. 1993; Sandlund et al. 1996). In analogy with BL there are some new data to suggest that EBV is especially associated with intestinal T-cell lymphomas of this type among adolescents and young adults in Latin America (Quintanilla- Martinez et al. 1997). Prospects for immuno- therapy with regard to the EBV-associated lymphoproliferations are very promising (Hes- lop et al. 1994; Rooney et al. 1995), but may well represent only the tip of the iceberg. Recent association of EBV with malignant soft-tissue tumours of the young (McClain et ul. 1995; Lee et al. 1995) further expands the spectrum of EBV-associated tumours in this age group.

EBV and HD Conclusive evidence of the causal role of EBV

infection and its adolescent manifestation, infectious mononucleosis, in adult H D was obtained from longitudinal cohort and case-control studies (Rosdahl et al. 1974; Kvde et al. 1979; Mueller et al. 1989; Lehtinen 1989) and from detection of EBV DNA and gene expression in malignant Reed-Sternberg cells ( Weiss et al. 1989;


Anagnostopoulos et al. 1989; Wu et al. 1990; Pal- lesen et al. 1991). Shortly thereafter the association was also confirmed for European, West Asian, North and Latin American cases of childhood HD (age under 10 years), especially for mixed cellularity (>go% positivity) and nodular sclerosing (50% positivity) subtypes (Ambinder et al. 1993; Armstrong et al. 1993). It is likely that the EBV-positivity is not age-dependent (Palles- en et al. 1993), although the opposite view exists (Armstrong et al. 1993). In any case we now know that in the RS-cells of HD EBV expresses, in addition to EBNA-1 and EBER, the latent membrane proteins LMPl and LMP2A/2B, i.e. con- stituents of type I1 latency (Griisser et al. 1994; Niedobitek et al. 1997).

Histology does not seem to influence the overall survival (0s) in childhood HD (Shankar et al. 1997). Unfortunately, however, the effect of EBV status on 0s was not considered in this study. The fact that expression of EBV LMPl (and the following immune response) confers 60% protection from fatal outcome in a multi- variate analysis of 0s in HD is perhaps the best evidence for the etiopathogenetic role of EBV in HD (Morente et al. 1997). There are also data to suggest that specific LMPl deletion mutants of EBV type 2, especially those able to evade immune surveillance, are related to HD appearing in immunocompromised individuals suffer- ing from mixed infections with EBV types I and 2 (Yao et al. 1996a, 1996b; Dolcetti et al. 1997). EBV-induced local immunosuppression is yet another virus-specified mechanism for evading immune surveillance (Frisan et al. 1995).

HLA-association of HD, and an increased risk that monozygotic twins as compared to heterozygotic twins will develop HD, constitute solid proof of the role of genetic susceptibility for HD (Mack et al. 1995; Taylor et al. 1996; Dorak et al. 1997). In the context of naso- pharyngeal carcinoma, which also follows the type I1 latency gene expression pattern of EBV, there is evidence of coevolution of the human species and EBV (de Campos-Lima et al. 1996). It is highly likely that this kind of evidence is also emerging for the HD-EBV relationship.

New infectious agents, diseases and disease associations

Human herpesvirus type 6 (HHV-6) causes exanthema subitum, but is also able to cause

congenital infections (Yumanishi et al. 1988; Au- bin et al. 1992). It is the most common perinatal infection and a major cause of hospitalization (Breese Hall et al. 1994). During the 1990s yet two more herpesviruses - HHV-7 (Frenkel et al. 1990) and the lymphotropic HHV-8 (Chang et al. 1994) - have been discovered. While most children become infected with the ubiquitous HHV-6, HHV-7, cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV) and EBV, infections with HHV-8 are rare (Clark et al. 1993; Osman 1994; Tanaka- Taya et al. 1996; Lennette et al. 1996). There is DNA and sero- epidemiological data to suggest that HHV-6 might substitute for EBV in HD and BL (Clark et al. 1990; Torelli et al. 199 1 ; Iyengar et al. 199 1 ; Bandobashi et al. 1997; Westergaard et al. 1997). In the immunocompromised, association of both HHV-6 and HHV-8 with lymphoproliferative disorders has been described (Krueger et al. 1989; Horenstein et al. 1997). However, while concomitant infection with the former might reactivate the replicative cycle of EBV (Flamand et al. 1993), the latter does not seem to interfere with the inert type I latency of EBV since this is found in HHV-8-positive primary effusion lymphomas (Horenstein et al. 1997). Thus, HHV-6 and HHV-8 may be able to complement the oncogenic action of EBV in the absence of and in spite of the presence of the virus, respectively.

Rates of hematological malignancies with mutations in tumor suppressor genes (TSG) p53 and RBI range from less than 5 to 30% (for review see Cline 1994; Wada et al. 1993), which suggests that in mutation-negative cases wild- type forms of the TSG products might be inac- tivated by viral oncoproteins. In fact, there is both in vitro and in vivo evidence of EBV and p53 interaction in BL (Lehtinen et al. 1992; Szekely et al. 1993). 25% of children with B-cell NHL have autoantibodies to p53 (Caron de Fromentel et al. 1987). The origins of the p53 autoantibodies are unknown, but mutations (Wada et al. 1993), or interaction with viral, bacterial or thereby induced proteins (Szekely el al. 1993, 1995; Dong et al. 1994; Paavonen et al. 1994; Parsonnet et al. 1994, Lehtinen et al. 1996; Smith 1997), perhaps even accumulation due to hypoxia (maternal/paternal smoking) (Graeber et al. 1994; Shu et al. 1996), are possible explanations.

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Until recently, evidence for an association of human retroviruses with hematological malignancies in the young was restricted to a few reported cases (Harrington et al. 1991; Delaporte et al. 1993; Levine et al. 1994). However, in the areas endemic for HTLV-I perinatal or childhood infection with the virus, the incidence of T-cell NHLs in young adults increases 100-fold compared to a 4-fold increase in the elderly (Cleghorn et al. 1995). The extreme rarity of HTLV-I and HTLV-I1 in western countries (Hollsberg & Haffler 1993; Brennan et al. 1993) does not preclude the possibility that as yet unknown retroviruses could be involved. A recent study on infants receiving transfusions shortly after birth (or in utero) suggested an infectious etiology for NHLs appearing in adolescents or young adults (Memon & Doll, unpublished results). Furthermore, a number of ATL cases appearing in HTLV-I-negative individuals also suggests that unknown retroviruses may be involved, although lack of antibody response in persistent infections with defective HTLV-I must be considered (Levine et ul. 1994; Hall 1994). The recent discovery of retroviral ma- terial in common viral vaccines (BSni et ul. 1996), as well as the fact that young hemophilia patients (aged 10 to 39) who were exposed to HIV have a 40-fold risk of developing NHL relative to the general population (Rubkin et al. 1992), should not go unacknowledged in this context.

Emerging infectious causes of childhood ALL Heritable ALL is rare (Hawkins et al. 1995;

Horwitz 1997), but the identification of HLA- associated susceptibility suggests a possible infectious etiology for ALL (Dorak et al. 1995; Dearden et al. 1996). Infections and/or increased susceptibility to infections occurring during the perinatal period or during the preschool age are associated with an excess risk of childhood leukemia (McKinney et al. 1987; Hartley et al. 1988; Petridou et a/. 1993). The latter may result from advanced maternal age (>35 years) (Mun- ning & Carroll 1957; Stewart et al. 1958; Mac- Mahon & Newill 1962) and/or being the first- born (Stewart et al. 1958; MacMahon & Newill 1962). Expression of superantigens following congenital or perinatal retroviral infections (Snow 1996) or common viral or bacterial infections at a delayed age ( Witherell et al. 1997) might fulfil Greaves’ hypothesis (1988) of antigen-driven proliferation of the B-ALL cells.

On the other hand, congenital or perinatal infection with oncogenic herpesvirus or retrovirus might fit the (Kinlen 1988; Kinlen et al. 1990) hypothesis of an infectious agent/disease spread/ clustering due to population mixing.

PROPOSAL FOR ACTION

Instead of providing conclusions, launching of a scenario (Fig. 1) and a proposal for action

Agent Crucial and/or complementary events Outcome

Mismatch between latent proteins and HLA Class-I and -11 antigens Polyclonal lymphoproliferation

malignant growth Herpesvirus Inappropriate” timing of exposure predisposing to monoclonal

Absolutely and/or relatively compromised immune function

(Ag-driven) lymphoproliferation

monoclonal malignant growth

Super antigen expression

Retrovirus Inappropriateb timing of exposure predisposing totcausing

Insertional mutagenesis and/or direct transformation ”Delayed (absolute or relative to other herpes group viruses). bCongenital or perinatal. Fig. 1. Scenario of viral leukemia/lymphomagenesis in the young.

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(Lehtinen 1995) seem warranted. A nested case- control study design within a large joint cohort of pregnant women (>700,000), where mor- bidity due to infections during consecutive preg- nancies and later leukemia and lymphoma mor- bidity in the offspring can be reliably assessed, needs to be designed. Following linkage with the population-based, nationwide Nordic Cancer Registries, Nordic Serum Banks that were established 15 to 25 years ago provide the desired joint cohort. Index mothers with offspring with childhood leukemias and lymphomas diagnosed after serum withdrawal will be identified and matched with control women with healthy offspring. The relative risk of leukemias and lymphomas associated with exposure to infection can be assessed by means of modern serology (Linde et al. 1990; Lehtinen et al. 1993, 1996; Leinikki et al. 1993; Soderlund et al. 1995; Tede- schi et al. 1995), molecular biology (Liiwer et al. 1993; Gan et al. 1994; Secchiero et al. 1995; Chang et al. 1994; Pyra et al. 1993) and epidemiology (Lehtinen 1995).

For many reasons the sensitivity and speci- ficity of the tests will vary even though the best methods available are used. This may make the comparison of the relative risk associated with different infections difficult, but the identification of an increased risk associated with a particular infection or a specific interaction of particular infections will nevertheless be possible. The identification of specific infections as causes of hematological malignancies in the young will hopefully pave the way for effective preventive measures.

The authors wish to thank Pauli Leinikki, Lyly Teppo and Helga Ogmundsdottir for their critical review of the manuscript.

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