in haematology - postgraduate medical journal · haematology n.t.j.o'connor...

Postgrad Med J (1990) 66, 595 - 611 © The Fellowship of Postgraduate Medicine, 1990

Reviews in Medicine

HaematologyN.T.J. O'Connor

Royal Shrewsbury Hospital, Mytton Oak Road, Shrewsbury SY3 8BR, UK.

Introduction

The commission to review the advances inhaematology for one year forces one to considerthe size of the task, in terms of papers published, itis enormous; for instance in 1989, the journal'Blood' had 16 issues comprising over 5,000 pagesand a total of some 3 million text words. Thisoutput by one journal reflects the overall growth inmedical publishing since the second world war (seeFigure 1). As it is not plausible that authors willrestrict their outpourings, any limit on this ludi-crous quantity of print must be imposed by anoutside body. In the first instance I favour theadoption of three proposals:- no applicant for a job should cite more than 6

publications (10 for full professors)- control of multiauthor papers and gift author-

ship by limiting the number of authors cited inIndex Medicus to the first six

- no Index Medicus citation for any article whosecost has been defrayed by the author paying pagecharges (e.g. $50 per page for Blood).This hobby horse dealt with, I shall attempt to

highlight papers published over the last year whichreflect growth areas in haematology and which maybe of interest to practising haematologists andphysicians with an interest in haematology. Myselection is personal; I have also attempted to putgrowth areas into perspective and to appraisecritically some of the published work.

Haemopoietic growth factors

There has been increasing interest in growth hor-mones (colony stimulating factors, or cytokines)which regulate the proliferation of bone marrowprogenitor cells and control the function ofmatureblood cells. Molecular biology has allowed theproduction of large quantities of recombinantfactors, which are now being introduced intoclinical practice.' It is becoming clear that the

various cytokines act within a complex network ofinter-reactions, thus, isolating the effects of oneparticular growth factor is difficult, and possiblyfutile since each cytokine operates within anenvironment produced by other growth factors.These cytokines exert their effect on target cells bybinding to high affinity cell surface receptors, whichare present in relatively low concentration onhaemopoietic cells.

(a) Erythropoietin

Erythropoietin is a glycosylated protein with amolecular weight of 34,000: over 90% of thehormone is produced by the kidney and its action islineage specific.23 In normal individuals this hor-mone is released in response to renal hypoxia and

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1948 1958 1968 1978 1988Year

Figure I Articles published and indexed in IndexMedicus (in thousands) for the years 1948, 1958, 1968,1978 and 1988 (data kindly provided by the NationalLibrary of Medicine, Bethesda, MD).

Correspondence: N.T.J. O'Connor, M.D., M.R.C.P.,M.R.C.Path.

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stimulates erythroid precursors in the marrow toincrease red cell production, providing a simplecontrol mechanism. Severe hypoxia is the stimulusfor erythropoietin production and indeed the hor-mone was first isolated from the urine of patientswith aplastic anaemia.4

Patients with end-stage renal failure are usuallyanaemic and may require regular transfusion.2 Thisanaemia is principally due to an impaired marrowresponse because oferythropoietin deficiency,2 andearly trials demonstrated the effectiveness of re-combinant erythropoietin therapy in reversingsuch an anaemia,5'6 thus making the patienttransfusion-independent and avoiding the poten-tial risks of regular blood transfusion: transmittedviral infection and iron overload.7'8 Erythropoietindosage should be increased slowly to try andprevent the development or worsening ofhyperten-sion.9 Delay in response to treatment impliesanother cause for anaemia, particularly an under-lying iron deficiency.7'9"' Recently, two reports onover 450 patients have proven the efficacy andsafety of this treatment,79 with patients having ameasurable increased exercise capacity and im-proved cardiac and respiratory function." There ishowever an increased risk of thrombosis offistulae,7'9 and a slight increase in other thromboticevents (stroke, myocardial infarction). Erythro-poietin therapy is therefore ofproven value but it isexpensive: at current costs around £5,000 perpatient per year.8 Obviously treatment is indicatedin transfusion-dependent individuals but it seemslikely that some form of rationing may need to beintroduced for other patients, and there is debateabout the criteria which should be used to evaluatea particular patient's needs. A related issue is thetarget haemoglobin level (since a high haemoglobinincreases the risk of thrombotic sequelae and ismore expensive to achieve). It has been suggestedthat a haemoglobin of 95-115 g/l may give mostbenefit without risk.8 It is of note that the haemo-static defect seen in renal failure'2 is reversed bynormalization of the haemoglobin with erythro-poietin therapy.13 Erythropoietin is also successfulin treating the anaemia seen in human immuno-deficiency virus (HIV) positive patients onzidovudine therapy' and in rheumatoid arthritis,although these latter patients do not benefit symp-tomatically.'4.(b) Granulocyte-macrophage colony stimulatingfactor (GM-CSF)

T-lymphocytes and monocytes both produce GM-CSF in response to inflammatory stimuli. GM-CSF is produced locally and is not detectable in theserum. GM-CSF acts locally as a multipotentialhaemopoietic growth factor stimulating produc-tion of granulocytes and macrophages.' GM-CSF

also regulates the function of neutrophils, eosino-phils and macrophages as well as inhibiting neutro-phil migration, thus acting to localize an immuneresponse.

In clinical trials GM-CSF has been used tocorrect the chronic severe neutropenia seen inpatients with both congenital and chronic severeneutropenia.'5 GM-CSF shortens the neutrophilrecovery time after chemotherapy-induced neut-ropenia,"'16 and its major application is likely to bein speeding up marrow recovery following chemo-therapy or bone marrow transplantation (BMT).This will thus reduce the number ofdays' antibiotictherapy that patients require but is unlikely to havemuch impact on mortality since relatively fewpatients die between day 10 and 21 post-BMT.GM-CSF treatment is generally well toleratedalthough there may be some bone pain, gastro-intestinal disturbances and itching.7GM-CSF may be of most value in patients who

would currently require autologous BMT. Thus inpatients with non-haematological malignancyGM-CSF may permit the use of very aggressivechemotherapy regimens without the need forautologous BMT.'8 Alternatively GM-CSF can beused to improve the harvest in patients undergoingautologous BMT: cyclophosphamide is given toinduce pancytopenia and is followed by GM-CSFwhich produces a dramatic increase in the numberof circulating stem cells. These cells can be har-vested by leucapheresis and have been successfullyused to achieve a rapid haematological recoveryafter lethal chemoradiotherapy.19 These approach-es are likely to increase the role of very high dosechemotherapy in the management of both haema-tological and non-haematological malignancies.

Trials of GM-CSF in patients with aplasticanaemia have shown an increase in the circulatingneutrophil numbers (1.5- to 20-fold) but there is noappreciable effect on the platelet count.15 However,the effect is short-lived and GM-CSF may actprincipally to mobilize marginated neutrophils,since there was no observable increase in themyeloid colony forming units. Clearly GM-CSFcannot be expected to exert a major effect if themarrow pluripotent stem cells are not healthy, andas withdrawal of the drug results in relapse,15 itwould seem that GM-CSF, given alone, has little tooffer in aplastic anaemia. Similarly, in the treat-ment ofmyelodysplasia GM-CSF has increased theneutrophil count. Unfortunately, as with aplasticanaemia, this effect is only observed when thepatient is receiving treatment and there is noappreciable effect on other cell lineages. 20 Lastly,in those patients with myelodysplasia and an excessof myeloblasts before starting GM-CSF thereappears to be a considerable risk of precipitatingthe development of acute leukaemia.2'Up to 25% ofpatients may develop antibodies to

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yeast-derived GM-CSF, because of the presence ofunprotected glycosylation sites.22 The clinicalsignificance of this retrospective finding is unclearbut it may limit the use of growth factors derivedfrom yeast, and perhaps other non-mammaliansystems.

(c) Granulocyte colony stimulatingfactor (G-CSF)

G-CSF is a relatively lineage-specific growth factorthat supports the differentiation of marrow pro-genitor cells which are committed to the neutrophillineage.' G-CSF has been successfully used toreverse idiopathic neutropenia,23 congenital agran-ulocytosis,24 drug-induced agranulocytosis25 and toinduce remission in hypoplastic acute myeloblasticleukaemia.26 G-CSF has also been used followingcytotoxic therapy and autologous BMT to reducethe period of neutropenia and thereby significantlyreduce the in-patient stay required.27 However, aswith GM-CSF this is unlikely to make muchdifference to procedure-related deaths. G-CSFtherapy has been shown to enable the delivery ofmore chemotherapy to patients, compared withcontrols in whom myelosuppression may delay thenext cycle of therapy.28 Its major benefit maytherefore be in permitting the delivery of more

chemotherapy to patients with malignant disease.More experimentally, G-CSF has been tried in

patients with myelodysplastic syndromes and pro-duced an impressive increase in neutrophil count,with no apparent risk of enhancing leukaemictransformation.29

(d) Other cytokinesThere has been less published work on othergrowth factors although interleukin 3 appears to beparticularly promising. This is a multipotentialgrowth factor which appears more potent thanGM-CSF at stimulating early marrow progeni-tors.' Clinical studies with this agent are currentlyin progress.

(e) Inhibitors ofhaemopoietic stem cellproliferationProteins which inhibit the proliferation of pluri-potent stem cells have recently been identified.30'3'These proteins are produced by macrophages andmay act to switch off cell growth stimulation andcould be used to keep haemopoietic stem cells fromentering the cell cycle during the administration ofchemotherapy, thereby protecting them from theeffects of cytotoxic drugs. Since marrow suppres-sion is usually the dose limiting factor in chemo-therapy regimens it can be seen that such agentswould have the potential to improve the treatmentof chemotherapy-sensitive neoplasms.31

Aetiology of acute leukaemia

Patients and their physicians are always keen tounderstand why particular malignant processesoccur. However, leukaemia is an uncommon eventso that the effect ofany postulated aetiological agentwill only be recognized as an increased risk com-pared with the normal population, i.e. an increased'relative risk'. It is important to realize that thenumbers of cases involved in a 'cluster' may be verysmall, and thus prone to random variation whichshould not be overinterpreted. Indeed, publicationof small studies may lead to considerable mediaattention and induce undue anxiety, as has recentlybeen observed in relation to the television pro-gramme on 'leukaemia and power lines'.3

(a) Radiation

One acknowledged aetiological factor for leu-kaemia is radiation: evidence for this associationcomes from the Japanese survivors of atomicbombs, individuals irradiated in utero, and patientsgiven high dose radiotherapy for ankylosing spon-dylitis.33 In contrast, diagnostic X-rays and radio-therapy for Hodgkin's disease have not been linkedto leukaemia, so it can be seen that a dosage effect isapparent.

Controversy particularly surrounds the appar-ent clustering of childhood acute lymphoblasticleukaemia (ALL) observed around some nuclearplants: particularly the reprocessing plant atSellafield in West Cumbria.34-3 Although the useof postal districts to detect such an effect is open toover zealous interpretation, sophisticated analysiswith a Geographical Analysis Machine confirmsthat there is a high incidence of childhood ALLaround Sellafield.37 In contrast, no leukaemia hot-spot appears to exist around nuclear reprocessingplants at Dounreay38 or Le Hague39 whilst there isan even bigger cluster in Tyneside which is morethan 50 km away from the nuclear industry." It hasalready been demonstrated that there is nosignificant risk of leukaemia or other cancers inradiation workers from Sellafield40 or other atomicenergy sites.41 It is also of note that the incidence ofHodgkin's and non-Hodgkin's lymphoma was notincreased.Gardner believed that radiation may be respon-

sible for some cases of childhood ALL andtherefore pursued the geographical link establishedat Sellafield, studying numerous parameters inALL patients compared with 'case-controls'.35,36Over a 35-year period there were 52 cases aged lessthan 25 within the West Cumbria health district.Nine ofthese were children born to men working atthe nuclear plant (17.3%) compared with casecontrols in whom only 41/277 (14.8%) had fathersworking at the plant. A close worked statistical

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analysis gave rise to the hypothesis of a linkbetween father's occupational exposure to radia-tion prior to conception (especially radiationdosage above 100 mSv) and leukaemia developingin the offspring (the relative risk being quoted as upto seven times that of a control population).3'36There is also limited experimental evidence tosuggest that such a mechanism may occur.4 How-ever, three caveats should be sounded: (i) thishypothesis is actually based on only 5 cases ofALL, (ii) there is also a risk of a first degreestatistical error, given the number of possibleassociations studied and (iii) a large study ofchildren born to the 7387 male survivors of theHiroshima and Nagasaki bombs did not show anincreased risk of leukaemia.43 In conclusion thistheory must be proven at other sites before beingaccepted, but until this question is settled thereduction in maximum exposure levels from50 mSv to 15 mSv should allay some of the anxietyin employees at Sellafield.44

It seems likely this matter will remain unresolvedfor some time to come, and until then the claims forcompensation against British Nuclear Fuels arepremature. Even if causation were proved by tort,the award of huge sums to a tiny group of childrenor their families would be in sharp contrast to allother patients with this disease, seeming bothillogical and unfair.

(b) Viruses

There is increasing evidence that viral infectionmay be an important step in the causation of somelymphoid malignancies. Thus adult T-cellleukaemia/lymphoma (ATL) is only observed inthose previously infected with HTLV I (humanT-cell leukaemia/lymphoma virus); HIV infectionpredisposes to high grade B-cell lymphomas andHodgkin's disease and Epstein-Barr virus isintimately concerned in the development ofBurkitt's lymphoma and possibly Hodgkin'sdisease. Therefore, in some instances viral infec-tions are a prerequisite for later leukaemogenesis.Viral infection may be central to the developmentofchildhood ALL, even ifleukaemia only occurs ina very small proportion of those exposed to thevirus, and the timing of viral infection may becrucial to the risk of a later leukaemia. Thus analternative explanation for the ALL cluster atSellafield is based on the finding that clusters havealso been observed around places considered fornuclear reprocessing plants but where no suchplant was built.45 Like Sellafield such sites aregeographically remote and sustained a largepopulation influx in the 1950s. Kinlen has sug-gested that people in this area had a low herdimmunity to common viral infections (as inmeasles) and that a rare response to one of these is

the development of ALL.4 This might also explainthe apparent cluster of childhood ALL seen in myhome county, Shropshire.47(c) Drugs and chemicals

Cytotoxic therapy, particularly with alkylatingagents is known to increase the risk of later acutemyeloblastic leukaemia (AML).4 This is partic-ularly recognized in patients who receive combina-tion chemotherapy for Hodgkin's disease: patientshave a cumulative rate of developing myelodys-plasia or leukaemia of around 10% by 10 yearsafter completion of therapy.49'50 There is a temporalrelationship to this risk in that it first becomesapparent one year after starting chemotherapy andhas disappeared a decade after stopping thesedrugs.49 The risk of alkylating agents (chloram-bucil, melphalan, cyclophosphamide) was againemphasized by a recent paper describing a 12-foldincreased risk ofleukaemia in patients who survivedovarian carcinoma after being treated with theseagents.5 Similarly, exposure to benzene has longbeen recognized as a potential cause of aplasticanaemia and a risk factor for AML.52'53 This gainedinternational prominence in the lay press when itwas found that some carbonated mineral waterscontained benzene and were withdrawn fromsupermarket shelves, even though the levels werenot outside recommended exposure limits.

Leukaemias occurring after chemotherapy arenotoriously difficult to treat and it has now beenshown that chemotherapy or benzene-associatedleukaemias are frequently accompanied by non-random chromosomal changes: especially loss ofpart of the long arm of chromosome 5 or 7, orcomplete loss of either chromosome.4 This com-bination of(i) leukaemia associated with defects ofchromosome 5 or 7, (ii) prior exposure to acarcinogen and (iii) a consistent time lag, impliescausality.4'54'55 Furthermore, it is tantalizing todiscover that the critical region on the long arm ofchromosome 5 contains the gene for numerousgrowth factors (granulocyte-macrophage CSF,interleukin 3, interleukin 5 and platelet-derivedgrowth factor),55 whilst the gene encoding eryth-ropoietin is situated at 7q22. It seems that thedeletion of these or related genes is central to thepathophysiology of these therapy related leuk-aemias.4

Indeed, cytogenetic abnormalities are beingincreasingly recognized as having prognosticimportance in patients with AML. Thus studieshave confirmed that cytogenetic abnormalitiesinvolving 5 or 7 are associated with a poor prog-nosis.56'57 Two large studies have also confirmed theassociations between various non-random cyto-genetic abnormalities and FAB subtypes ofAML:t (8;21) with M2 AML, t (15;17) with M3 AML,

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inversion 16 with M4 AML and eosinophilia. Thislatter leukaemia is usually found in youngerpatients and has a relatively favourable out-look.56'57 More recently, deletions from the shortarm of chromosome 9 have been described inpatients with acute lymphoblastic leukaemia.58This deletion site is close to the genes coding forinterferon and it has been suggested that thesedeletions may lead to the loss of a tumour suppres-sor gene, possibly even the interferon gene.5

Treatment of acute leukaemia

There continue to be reports of large scale trialswhich increasingly show improved results,59'60 andare usually based at many centres. This advancehas relied on the use of aggressive combinationchemotherapy, which leads to prolonged pan-cytopenia requiring considerable support for infec-tive and bleeding episodes. It should be emphasizedthat much ofthe improvement is attributable to theprovision of better supportive care during chemo-therapy-induced pancytopenia.61 However, thechemotherapy is clearly ofprimary importance andin a review of over 4000 children with acutelymphoblastic leukaemia it was clearly shown thatpatients entered into trials had a better long termsurvival than those not in trials.6 Equally impor-tant, it was shown that patients treated in smallcentres fared as well as those in large centresprovided that they were entered into trials.60The treatment of acute leukaemia can be divided

into 3 phases: supportive care, induction of remis-sion and further therapy.62 Clearly the outlook forpatients who fail to enter remission is bleak, andmost studies concentrate on the best way to treatminimal residual disease. The 'best option',chemotherapy or bone marrow transplantation(BMT), for a particular patient, depends on manyfactors: age, underlying disease, disease status,presence of adverse prognostic factors and donoravailability.6364 Confusion over the best choice isconfounded by protagonists of one therapeuticoption publishing over-optimistic results based ona small series of highly selected patients andproviding embarrassingly short follow-up. Inmany papers it is difficult to find the time ofminimum follow-up and this deficiency is obscuredby statistical methods which allow the authors to'extend' the follow-up and quote an actuarialrelapse risk at some future date. In 1987 a Lanceteditorial advocated that an acceptable format forcommunications on bone marrow transplantationshould include a minimum 2 year follow-up onevery patient65 but this is usually woefully lacking.Large ongoing studies should help to answer thequestion ofwhich patients should be offered BMT,and when. However, most of the trials are not

considering the impact which haemopoietic growthfactors (vide supra) or interleukin 2 therapy6 maygive.

(a) ChemotherapyThe long term efficacy ofchemotherapy in patientswith acute myeloblastic leukaemia (AML) is onlynow becoming apparent, since previous studieshave reported on cohorts with a relatively shortfollow-up. The CALGB group has now publishedprolonged follow-up on 760 patients who enteredremission of AML:67 these cases were on main-tainence treatment. Unfortunately median remis-sion time was only 13 months, and 3 years post-remission only 25% patients remain disease-free.Furthermore these data suggest a continual relapserate up to 8 years post-remission and, depressingly,there was no identifiable disease-free plateau whichwould be expected if patients were being cured ofAML by chemotherapy alone.67 These results wereconfirmed in a Danish study of patients who werein first remission 3 years from obtaining thisremission.6 However, this study is more optimisticin showing that the relapse rate after 3 years isrelatively slow, so that 60% of these patients willappear 'disease free' 5 years later (i.e. 8 years afterdiagnosis).(b) Bone marrow transplantation (BMT)BMT may be carried out using a matched siblingdonor (allogerieic) or the patient's own marrow maybe reinfused (autologous). Autologous BMT offersthe possibility of myeloablative chemo/radio-therapy without the risks of graft-versus-hostdisease (GvHD).65'69'70 However, in patients withmarrow involvement such an approach will lead tothe reinfusion ofmalignant cells and, this has led tothe introduction of purging protocols, althoughthese are of unproven value.65 Lately, a combina-tion of ether lipids and hyperthermia to 42°C forone hour has been shown to inhibit leukaemicprogenitor cell growth to less than 3%.71 Analternative strategy relies on the premise that,following cytotoxic therapy, normal, rather thanleukaemic, stem cells are released into the circula-tion. Thus patients may be given cytotoxic therapyto induce pancytopenia and circulating stem cellsare then harvested by leucapheresis: this approachhas yielded variable results.

In patients who undergo allogeneic BMT there isincreasing evidence that GvHD and its preventionare crucial elements in obtaining a cure of theunderlying disease. Although GvHD may beassociated with life-threatening complications itappears to be important as 'immunotherapy' foracute leukaemia.72 Thus prophylaxis againstGvHD may influence the leukaemic relapse rate:

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the most commonly used techniques involveregular methotrexate therapy, T-cell depletion orcyclosporin. Results from over 600 patients haveshown that methotrexate reduces the risk ofleukaemic relapse in comparison with cyclosporinor T-cell depletion of the donor marrow,73 and theevidence suggests that this is due to an anti-leukaemic effect of methotrexate rather than lesseffective suppression of GvHD.73One group has attempted to harness the graft-

versus-leukaemia effect of GvH by inducing'GvHD' in patients undergoing autologousBMT.74 Although this appears to ignore thedefinition of GvHD,75 the authors claim to havestimulated host lymphocytes to be cytotoxicagainst self. Clearly this work needs furtherclarification.Comparisons between allogeneic and auto-

logous BMT for patients aged less than 50, in firstremission of AML, are being carried out in manymulticentre trials. Early data from small studiessuggests that allogeneic BMT gives a higher pro-bability of prolonged disease free survival,76'77although studies on such small patient numbersmust be regarded with some caution. Althoughallogeneic BMT is proven to offer a good chance oflong term cure, this has not yet been demonstratedfor autologous BMT; indeed there is no convincingevidence that survival curves reach a plateau phaseafter autologous BMT.70 It is quite possible thatautologous BMT, for AML, is no more effective atachieving a cure, than 'high dose' consolidationtherapy and is merely prolonging the duration ofremission before late relapse. Thus autologousBMT should only be carried out within the contextof a scientific study, so that its role in acuteleukaemia can be properly assessed.65'70

Allogeneic BMT is only feasible in patients agedless than 50 who have an HLA-identical sibling.Only 35% ofpatients will have a matched sibling toact as a potential marrow donor, so there has beenan increasing interest in the use of matchedunrelated donor (MUD) BMT.78 This procedure isvery experimental and carries a higher risk ofGvHD and hence death than matched siblingBMT. My experience with 14 patients subjected toMUD BMT has been bad: only one patient sur-vived longer than one year. These patients are atrisk of developing savage fatal GvHD ('the blazingspitfire syndrome', a term coined by Francis Mat-they). Therefore the decision to perform a MUDBMT in a patient with AML in first remission, or infirst chronic phase ofCML is contentious. I believethis experimental approach should be restricted toonly one UK transplant centre, so that expertisecan be concentrated in this unit and the value ofMUD BMT be properly evaluated.

Aggressive therapy for multiple myelomaThe treatment of this depressing condition hasshown little improvement over the last several yearsand pulsed doses ofmelphalan and steroids remainthe mainstay of treatment.79 In most patients theparaprotein level falls until a plateau is reached;therapy should then be discontinued. Unfor-tunately, only two thirds of patients respond andeven in these indviduals disease progression even-tually occurs, so that death is inevitable. Thus themedian survival of patients diagnosed as havingmyeloma is only 3 years. Comparing differenttreatment protocols is difficult because of theheterogeneity of this disease, poor markers forprognosis (or staging), and because there has beenno accepted criteria by which to judge diseaseresponse. Lately two groups have suggested broadlysimilar criteria for the definition of 'completeremission' which are: (i) no paraprotein in blood orurine, (ii) less than 5% plasma cells in the marrowand (iii) that this state should persist for 3months.80'8' The universal adoption of this or of asimilar definition would certainly simplify com-parisons between different studies. Unfortunatelythe problem of a useful and acceptable stagingsystem remains. Recent papers have suggested twoways in which the bleak outlook of myeloma maybe improved.

(a) Intensive therapyfrom diagnosisIn younger patients pulsed courses of cytotoxicdrugs may be used to reduce dramatically thetumour burden. The regimens used rely on acombination of vincristine, adriamycin and highdose steroids (similar to the VAD regimen pilotedby Barlogie.82). Such an approach is only appropri-ate in individuals who are able to withstand suchtreatment, and should probably be restricted tothose aged less than 60. The major risk of suchtherapy is infection secondary to neutropenia, soprophylactic cotrimoxazole may be used. Up to50% of patients may obtain a complete remis-sion.80'81'83 and this may give a longer plateau phasebefore disease relapse.

(b) Maintenance ofremission orplateauphase

Autologous bone marrow transplantation is beinginvestigated as a means of consolidating completeremission, once achieved. This procedure isrelatively well tolerated and early studies suggestthat it may prolong disease-free survival.80'84'85An alternative is the use of interferon as

'maintenance' therapy in patients who reachplateau phase of their myeloma. One preliminarystudy suggested that patients who received alphainterferon had a longer survival than controls.86

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There are some worries about this work viz. (i) thenumber of patients was small and the diseasecourse of myeloma is very variable79 and (ii) thecontrol group fared much worse than one wouldusually have expected. However, interferon mayprove to be of benefit in myeloma and its role in themanagement of this disease is now being evaluatedin large trials.

These approaches to treatment are experimentaland controversial: indeed a recent Swedish studyconcluded that melphalan/prednisolone treatmentis as useful as the more complex multidrugregimens.87 This emphasizes the need to restrictnew therapies to patients who are entered into largewell organized multi-centre trials.

In utero bone marrow transplantationThe feasibility of using liver haemopoietic cells toundertake bone marrow transplantation (BMT) inmonkey fetuses within the womb has been demon-strated.88 Transplants were carried out in 5 monkeyfetuses at around 8 weeks' gestation, opposite sexdonors being used so that karyotype analysis couldbe used to define successful engraftment. Suchanalysis showed successful engraftment in 4 of 5monkeys with 5-15% ofmarrow precursors beingof donor origin and persisting at this level for up to2 years post-BMT.88 This procedure has beenproposed as potential therapy for patients with a

congenital haemoglobinopathy in utero. This workis an impressive tour-de-force but I rate it as illconceived as the Sinclair C5 (a tiny electric poweredmotorcar introduced in the UK in 1985, whichredefined the concept ofmarketing failure). Firstly,the procedure would be expensive and divertresources from other needs but more worryingly itwould enable the germ cells to be carried through tothe next generation, in complete disregard ofDarwinian natural selection.

Chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is a myelo-proliferative disease with a typical cytogeneticabnormality: the Philadelphia chromosome. Thisfusion chromosome is formed by a translocation ofthe oncogene c-abl from chromosome 9 to thebreak point cluster region (bcr) on chromosome 22,t (9:22). This translocation gives rise to a bcr/ablP210 protein and it has recently been shown thatthis protein can induce a myeloproliferative state inmice: analogous to CML.89 Failure to detect thePhiladelphia chromosome, using standard cyto-genetic methods may be caused by a much smallertransfer of material from chromosome 9 to 22; sothat proof of the bcr/abl translocation relies on

molecular biological techniques.90 An alternativeexplanation for Philadelphia negative CML is thatthe haematological diagnosis is wrong: thus reviewof a small series demonstrated that if no bcr/abltranslocation was detectable, none of these casesfulfilled the criteria for the diagnosis of CML.91The myeloproliferative state is typically charac-

terized by splenomegaly, marked leucocytosis dueto an increase in mature and immature myeloidprecursors (usually in the range 50-400 x 109/1),thrombocytosis, moderate anaemia and a grosslyhypercellular bone marrow. Treatment of this'chronic phase' is straightforward and relies onpulsed doses ofhigh dose busulphan or continuoushydroxyurea. Unfortunately chronic phaseCML isan unstable state and acute leukaemia supervenesin nearly all patients. This blast transformationusually occurs within 3 years ofdiagnosis, althougha few patients may remain in prolonged chronicphase.92'93 Painstaking efforts have been made toestablish prognostic markers to predict the onset ofblast crisis94 but they are of limited value, since thechange appears to be random. One of the mostvaluable prognostic criteria may be the duration offirst remission as an indicator of the probablelength of chronic phase (i.e. the time betweenachieving a white cell count of less than 10 x 109/1and the need for more therapy).9293 Four fifths ofthe acute leukaemias which arise in these patientsare myeloid and resistant to therapy, with deathusually occurring within a few weeks.

Considerable attempts have been made to im-prove the bleak outlook for CML but the onlyproven advance has been the introduction ofallogeneic bone marrow transplantation (BMT).BMT offers the possibility of cure9596 but is onlypossible in a minority of patients and it is worryingthat many of these may undergo a cytogeneticrelapse of their disease.9596 The presence of theleukaemia specific bcr/abl translocation and theintroduction of the polymerase chain reactionmeans that residual CML cells can be detected at aconcentration ofless than 1/10,000.97 The incidenceof cytogenetic relapse is unclear but one group hasdemonstrated a translocation in 11/12 patients whoappeared to be in cytogenetic remission followingBMT98 and although the significance of a cytogen-tic relapse is not yet proven it may predict diseaserelapse. Frank leukaemic relapse is particularlyobserved in patients who undergo a T-cell depletedtransplant.96Matched sibling BMT is only feasible in 35% of

patients under the age of 50, so efforts have beendirected at other treatment modalities which mayprolong the duration of chronic phase CML.Recently there has been considerable interest in theuse of alpha interferon which controls the myelo-proliferative state in 70% of cases, and earlyreports suggest it may delay the onset of blast cell

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crisis," with the Philadelphia chromosome be-coming undetectable in a minority ofcases. As 30%of patients do not respond to interferon, scepticsmight suggest that response to alpha interferonmerely identified those patients who belong to arelatively good prognostic category and who cantherefore be expected to remain in remission forlonger than non-responders. Other worries aboutthe potential value of this treatment are that asignificant number of patients develop antibodiesto recombinant interferon,'00 and side effects maybe severe enough for many other patients todiscontinue therapy (vide infra). The results oflargescale trials of this drug are awaited with interest.

Essential thrombocythaemiaEssential thrombocythaemia (ET) is a diagnosis ofexclusion and can only be properly made if there isno underlying cause for a reactive thrombocytosis.Correct evaluation of a patient thus relies onexcluding underlying carcinoma, iron deficiency,active blood loss, infection or any otherinflammatory process. A bone marrow examina-tion must also be carried out, in order to excludethe Philadelphia chromosome. However, evenrigorous care will leave the diagnosis unclear insome patients; typically with a platelet count in theregion 800-1200 x 109/1. A recent paper on thediagnosis of ET encourages the use of positivediagnostic criteria to differentiate this disorderfrom a reactive thrombocytosis:'01 the scoringsystem is based upon five variables as shown inTable I.

Effective treatment of ET relies on adequatecontrol of the platelet count, although there is noconsensus on whether the level should be held at800, 1000 or 1200 x 109/1. This can be readilyachieved with pulsed doses of busulphan or con-tinuous low dose hydroxyurea. These drugs doimpart a very slight increase in the relative risk ofdeveloping leukaemia after several years, and thishas led to trials ofother therapies. Alpha interferon

Table I Criteria for the diagnosis of essential throm-bocythaemia and the scores allocated for each feature

Splenic enlargement on scan 2Unstimulated BFU-E (*) derived clones from 2

peripheral bloodElevated platelet nucleotide ratio 1(ATP:ADP > 3.25)

Elevated platelet distribution width (PDW > 17) 1Clinical ischaemia present 1

A score of 3 or more is highly suggestive of primarythrombocythaemia whereas a score ofless than 3 suggeststhe presence of a reactive thrombocytosis.'0'(* BFU-E denotes blast forming units-erythroid).

has been shown successfully to control the throm-bocytosis seen in ET and other myeloproliferativestates.'02-"4 Although such therapy may controlthe thrombocytosis, the clinician should be wellaware of the side effects which may be suffered bythe patient; particularly psychological problemswhich may persist until the interferon has beendiscontinued. As ET is a disease which can beexpected to run an indolent course and is easilycontrolled with chemotherapy, the issue of qualityof patient life should rate very highly with thehaematologist. Personally, I believe it is wrong tosubmit patients over the age of 60 to regularinjections which may carry a constellation of sideeffects. This may be especially important since aproportion of patients will develop neutralizingantibodies to recombinant interferon, andtherefore resistance to therapy.l00'105 It should alsobe pointed out that the cost oftreatment per patientper year may be around £2250.Although the aetiology of ET is unclear, an

interesting study claimed to have detected retro-virus within the platelets of 11 out of 11 patientswith myeloproliferative disease with comparison toonly 1 out of 7 control subjects."06 The validity ofsuch a finding needs to be confirmed since thetechniques used may give rise to false positivity, butif this finding is confirmed it raises interestingquestions as to the aetiology of these disorders.

Chronic lymphocytic leukaemia

The heterogeneity of this disease has beenemphasized, including the importance of makingan accurate diagnosis based on the observation ofasustained lymphocytosis (usually greater than10 x 109/1): which is due to a clonal lymphoidproliferation, usually of B-cell origin. The Interna-tional Workshop on chronic lymphocyticleukaemia (CLL) has recommended the adoptionof the Binet staging system, rather than the olderRai system'07 (see Table II). This system is easier to

Table II Binet staging system for chronic lymphocyticleukaemia and data on median expected survival for each

group of patientsMedian survival

Stage Criteria (months)A Less than 3 areas involved > 120B Three or more areas 61C Haemoglobin < 100 g/l 32

Platelets < 100 x 109/1N.B. The areas assessed include the cervical, axillary

and inguinal lymph nodes (whether unilateral orbilateral), the spleen and liver.

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apply and is better at discriminating betweenpatients with markedly different prognoses.They further suggested the acceptance of stan-

dard criteria for judging response to therapy.'08Halfof the deaths in patients with stage A CLL areunrelated to the disease and the InternationalGroup reported on the prognostic features of stageA CLL.'07 Patients were subdivided into those witha lymphocyte count of <30 x 109/1 and haemog-lobin > 120g/l stage A'; or stage A" if thesecriteria were not met. Data on over 900 patientsshowed that survival for patients with stage A'disease was identical to that of the rest of thepopulation. There was also proofthat patients withearly disease may not require any therapy,confirming the widely held view that patients withearly stage A CLL should not be subjected totreatment.In contrast, the French study on patients with

advanced CLL (stage C) has been updated and thisconfirmed an earlier report which showed thatmonthly combination chemotherapy according tothe CHOP protocol gives a markedly improved 3year survival compared to COP chemotherapy'9(C = cyclophosphamide, H = adriamcyin, O = vin-cristine and P = prednisolone). Thus adriamycin(doxorubicin) appears beneficial in patients withadvanced CLL. A new drug, fludaribine, may alsorepresent an advance in CLL, although the data arepreliminary. One study showed a 50% response inthe CLL, and this was achieved without unduemyelosuppression. l0 Side effects included infectionand less commonly a neuropathy.

Cell lineage of Hodgkin's disease

The nature of the malignant cell (Reed Sternbergcell or RS cell) has been controversial for manyyears - this is partly because most cases have arelative paucity ofRS cells.1' Two approaches mayhelp overcome this problem: firstly the isolationand purification of RS cells from lymph nodes"2and secondly the application of molecular bio-logical techniques. These latter studies dependupon rigorous criteria being imposed before a caseis designated as true Hodgkin's disease; moststudies are then unable to find evidence of either B-or T- cell lineage as judged by immunoglobulin orT-cell receptor beta chain gene rearrangement.'3The importance of a correct diagnosis beforeproceeding to genotypic analysis cannot be over-emphasized: the diagnosis of Hodgkin's disease is amorphological one, and if the tissue studied hasbeen wrongly interpreted the results will be mis-leading. This is exemplified by papers which fail tofind evidence ofT-cell receptor gene rearrangementin T-cell lymphomas,"4 and is best described usingcomputer terminology 'garbage in, garbage out'.

However, a recent paper using a monoclonalantibody to an epitope of the T-cell receptor betachain claimed to show in situ positivity in around30% of RS or Hodgkin's cells."5 These datasuggest that Hodgkin's disease is T-cell derived butit should be treated with caution since no controltissue appears to have been studied.

Studies using in situ hybridization have shownevidence of Epstein-Barr virus (EBV) DNA withinRS cells from a number of patients with Hodgkin'sdisease,"6 and the incidence of EBV infection ismuch higher in HIV seropositive patients whodevelop Hodgkin's disease.'7 This is more sugges-tive ofa B-cell lineage for the RS cell and also raisesintriguing questions about the aetiology of thisdisease.

Iron chelation therapyIron overload is observed in patients who requireregular blood transfusion (e.g. thalassaemia majoror chronic red cell aplasia) and this leads tohaemosiderosis; with cardiac failure, cirrhosis,diabetes mellitus and a slate grey skin. Patients whoare untreated generally die of heart failure beforethe age of 25. Venesection cannot be used in thesepatients but effective removal of iron (chelation)with subcutaneous desferrioxamine has radicallyimproved the survival of these patients."8 Thistreatment relies on subcutaneous infusion for 5nights a week, year in year out. This is unpleasantfor the patient and poor compliance results in earlydeath.

Lately an oral iron chelator designated LI hasbeen introduced into clinical practice and earlyreports suggested it was safe and that it gave rise toa negative iron balance."9 However, doubts havebeen raised about the safety and efficacy of thisdrug:120 one patient developed prolonged profoundpancytopenia due to trilineage aplasia whilst tak-ing LI.121'122 In this case the patient had absoluteneutropenia for at least 17 days and she onlysurvived her life-threatening infection because hermarrow function regenerated. This complicationhas been observed despite less than 120 patientshaving been treated'23 and this suggests that thisparticular drug carries an unacceptable risk.'24However, Ll does point to the possibility of oralchelation therapy, and it is to be hoped that a saferand effective oral iron chelator will soon bedeveloped.

Prophylaxis of rhesus haemolytic disease of thenewborn

Rhesus negative_women who give birth to rhesuspositive children may receive a transplacental

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transfusion of red cells and this particularly occursat term. Sensitization to rhesus D may lead tohaemolytic disease of the newborn (HDN) insubsequent pregnancies and therefore rhesusnegative women receive anti-D immunoglobulin atterm. This mops up fetal red cells within thematernal circulation, thus reducing the incidence ofrhesus sensitization to less than 10% of thatpreviously observed. However, sensitization torhesus D may occur during pregnancy, and give riseto new cases of HDN. A recent large study hasconfirmed the value of giving anti-D immuno-globulin to rhesus negative women at 28 and 34weeks of pregnancy, as well as at term.125'126 Thisprocedure has been shown to be effective in reduc-ing the incidence of rhesus immunization and issafe.126

Haemophilia A

Effective treatment of haemophilia A relies on theuse of anti-haemophilia factor (VIIIc). Howeverthis carries the risk of transfusion-associated viralinfection, particularly with human immunodefici-ency virus (HIV) and non-A, non-B hepatitis.'27The current strategy to prevent such infectionsrelies on dissuading 'high risk' blood donors,screening blood donations and, more recently, theintroduction of heat treatment. Although theseapproaches appear to prevent either ofthese partic-ular infections128 it can be seen that synthetic factorVIIIc would be even safer. Recombinant anti-haemophilia factor has now been prepared andsuccessfully used in patients.129 There was a cleartherapeutic and laboratory response and neitherpatient developed significant antibodies.129 Theadvantage ofrecombinant factor concentrate is theabsolute certainty that it carries no contaminatingviral infection. However, current technology isunable to produce factor VIIIc in clinically usefulquantities.

Desmopressin (DDAVP)This agent can be given by slow intravenousinfusion and has been shown to improve haemos-tatic function by increasing the levels offactor VIIIprocoagulant and von Willebrand factor.'3 Thus itcan be used in patients with mild haemophilia orvon Willebrand's disease,'30 in the bleedingassociated with renal failure,'' and in the post-operative situation.'32 As DDAVP may control ahaemorrhagic state without recourse to bloodproducts it has proved extremely useful. Unfor-tunately there have been recent reports of acutemyocardial infarction immediately followingDDAVP. Therefore this drug must be used with

extreme caution in the elderly and those witharterial disease.'33

Rare causes of thrombocytopenia

Heparin-induced thrombocytopenia (HIT) mayoccur within a few days of starting heparin, when itis usually not severe and is caused by impuritieswithin the preparation. However, late onset HIT isa life-threatening condition occurring from 8 to 25days after starting heparin. This disorder has animmunological basis and patients have a heparin-dependent IgG antibody which induces plateletaggregation: clinically there is severe throm-bocytopenia and massive thrombosis.134 A recentcase report described the successful use of int-ravenous immunoglobulin to reverse the throm-bocytopenia and which resulted in a rapid clinicalimprovement. 35Acquired amegakaryocytic thrombocytopenia is

a rare condition, which may herald the onset ofaplastic anaemia or myelodysplasia.'36 Cyclicalamegakaryocytic thrombocytopenia is even rarer,and a recent article describes such an entity andimplicates an antibody that selectively blocked theaction of GM-CSF on megakaryocyte precur-sors.137

Platelet transfusion therapyA recent consensus statement by the NationalInstitute of Health emphasized the value of suchtreatment in patients with thrombocytopenia att-ributable to chemotherapy or aplastic anaemia.'38In contrast, platelet transfusion therapy (PTT) isgenerally not required in patients with consump-tion thrombocytopenia, since the bleeding disorderis not so severe and survival of transfused plateletsis short.'39 Although a 6 unit transfusion might betheoretically expected to raise the platelet count by60 x 109/1, in practice an increment of 40 x 109/1 ismore usual.'39 Lately it has been shown thatincubating platelet concentrates at 37'C for 1 hourbefore transfusion gives an increase in the inc-remental platelet count of28%. 40 Thus the routineuse of warmed platelets would reduce the numberof platelet concentrates required by as much as25% with considerable savings in the workload oftransfusion centres. This would also reduce thenumber of donors to whom one patient wasexposed; although it appears that this does notreduce the incidence of either alloimmunization ortransmission of viral infection.'39'141

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Tranexamic acid

This antifibrinolytic agent has been used for someyears to delay clot breakdown and hence improvehaemostasis. It can be given either by mouth or

intravenously and is of proven value in patientswho have thrombocytopenia or platelet functiondisorders (such as Bernard Soulier disease).142Recent papers have drawn attention to otherconditions in which tranexamic acid (TA) may behelpful.

(a) Acutepromyelocytic leukaemia (APL)

This subtype of acute myeloid leukaemia is desig-nated M3 and characterized by an excess ofpromyelocytes with cytoplasmic granules, whichcontain a procoagulant. These patients may pres-ent with a disseminated intravascular coagulation,which usually worsens immediately after startingcytotoxic therapy, since these leukaemic cells are

lysed, thus initiating the coagulation cascade.Heparin therapy has been shown to improvesurvival in patients with APL.'43 More recently TAhas been used successfully in such patients, leadingto fewer bleeding episodes and a reduction in thenumber of platelet transfusions.44

(b) Anticoagulant patientsPatients who are on long term warfarin, forexample those with mechanical valve prostheses,are at risk of prolonged bleeding after dentalsurgery. In these patients, in whom warfarin can-not be safely discontinued, an aqueous solution of4.8% TA used to rinse the mouth four times a daysignificantly reduces the number of bleedingepisodes and is effective in preventing bleeding. 45

(c) ThrombocytopeniaA 4.8% aqueous solution ofTA is also effective inreducing the mouth bleeding which may be seen inpatients with thrombocytopenia due to bone mar-row failure.

Transfusion associated graft-versus-host disease

Viable lymphocytes are transfused every time thata patient receives a blood or platelet transfusion.These lymphocytes are virtually always rejected butif this fails to happen and engraftment occurs, thendonor lymphocytes will recognize the host as

foreign. This will result in a transfusion associatedgraft-versus-host disease (TA-GvHD). Untilrecently this disease had only been recognized inseverely immunocompromized patients, includingthose with severe combined immunodeficiency

disease, bone marrow transplantation (BMT), andpreterm newborn infants. The disorder was alsodescribed in less than 1 in a 1000 patients receivingintensive chemotherapy for malignancy.'46TA-GvHD is underdiagnosed because many

clinicians are unaware of its existence and theclinical picture may be variable. However, anypatient who develops aplasia within 30 days ofreceiving blood products may have TA-GvHD.Before last year only 70 cases had been describedand all but 4 appeared to be immunocompromized.Lately Japanese workers have documented 96 casesof TA-GvHD following cardiac surgery'47 (anincidence of 1/660); although at present it isunresolved whether cardiac surgery is only a risk inJapanese cases, since only one case of TA-GvHDhas been reported outside Japan.TA-GvHD occurs from 4 to 30 days post-

transfusion of blood products and resemblesGvHD seen post-BMT in that it affects the skin,liver and gut. Typically the patient develops fever,gross erythroderma, obstructive jaundice and diar-rhoea. However, in contrast to patients post-BMT,the lymphocytes are not marrow derived, andtherefore recognize the host marrow as 'foreign',and this results in a profound aplastic anaemiawhich is rapidly fatal.

Typically, patients with TA-GvHD go downhilland die, so that chronic TA-GvHD has only beendescribed in one patient.'46 Supportive therapy isgenerally undertaken coupled with high dosesteroids or cyclosporin; this treatment is not ofproven benefit. Since there is no effective therapy ofTA-GvHD it is important to recognize the risk oftransfusion in an individual with impaired cellularimmunity. Adequate prophylaxis relies on theirradiation of blood products to 15 Gy, this dosagewill prevent lymphocyte proliferation without har-ming red cell or platelet function.'4 This precau-tion must also be extended to blood products givento patients during bone marrow harvest for anautologous BMT, since there is a high risk oftransfused lymphocytes being harvested and latergiving rise to TA-GvHD.'48

Transmission of infection by blood transfusion

(a) Human immunodeficiency virus (HIV)

Transfusion of blood or factor concentrates hasbeen associated with the transmission of HIVinfection, both before the introduction of HIVscreening for all blood products in 1985'49 and invery rare instances since then.'5 The prolongedincubation time from transfusion to developingfull-blown AIDS (probably around 6-8 years)means that there are many individuals who areHIV seropositive but remain clinically well. At

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least 500 cases of transfusion-associated AIDShave been diagnosed and a recent review estimatesthat a further 1500 cases of AIDS might beexpected.'5 Fortunately this figure is a large over-estimate since 'post-transfusion mortality' is high.However, it does indicate that we should expect tosee many more cases of transfusion-associatedAIDS than we have up to now.'49On a more optimistic note a large European

study has looked at the incidence of HIVseroconversion in multiply transfused thalassaemicpatients since 1985. Of nearly 3000 patients whowere transfused with over 96,000 units ofblood, noHIV sero-conversion was detected.152

(b) Hepatitis C (HCV)

Post-transfusion hepatitis is a significant cause ofmorbidity and in the USA occurs after 10% of alltransfusions. It accounts for 20% of all cases ofacute hepatitis, and commonly leads to chronicliver disease.53 Early work had shown that theagent responsible for most cases of 'non-A, non-Bhepatitis' was a virus sensitive to organic solventsand less than 80 tm in diameter, leading to theprediction that it would be a small RNA virus.154'155Using molecular biological techniques a putativevirus has been isolated and a test to detect thepresence of antibody developed.156 This test hasbeen shown to identify correctly the majority ofcases of post-transfusion non-A, non-B hepatitis,and the virus is now designated hepatitis C.156Studies in different populations have confirmedthat most post-transfusion hepatitis (PTH) is at-tributable to HCV.'57"'58 Further studies have beencarried out in high risk populations and HCVpositivity is seen in around 70-80% of haemo-philiacs,158-160 patients with chronic PTH158 anddrug addicts.158 Surprisingly, only a relatively smallproportion ofSpanish HIV sero-positive homosex-uals are HCV positive.'58 Lately, an elegant pro-spective study proved that recipients of anti-HCVpositive blood products had a 20-fold increasedrisk of developing PTH.'6' These authors alsocalculated that HCV antibody testing would be63% efficient at preventing PTH, although the testmay give false negative and false positive results.161Thus individuals may lose their HCV antibodypositive status, although presumably remaininginfectious.159'6' Other donors may show a falsepositive test, and currently the only way to confirma positive anti-HCV test depends on proving thepresence of virus within the blood: this is notpossible since the viral sequence ofHCV has not yetbeen published.The introduction ofa screening test for HCV has

considerable implications for the blood transfusionservices, since preliminary studies suggest thataround 1% of donors are sero-positive.162

Therefore the routine use ofsuch a test will contractthe size of the donor pool and raise the spectre ofcounselling individuals who are well but possessantibody to HCV. An alternative suggestion thatdonations should continue to be taken from theseindividuals but the blood should then be discarded,seems impractical.

(b) Cytomegalovirus (CMV)CMV is carried within the lymphocytes of sero-positive individuals. CMV infection is often sub-clinical and therefore most blood products are notscreened for CMV status. However, in neonatesand severely immunocompromised individualssuch an infection may be fatal: so that CMVnegative blood products should be used.'63 Analternative strategy is to transfuse the blood prod-ucts through a white cell filter and a recent studysuggested a dramatic reduction in CMVseroconversion.164 However, this study has beencriticized as having a very high incidence ofseroconversion amongst the control group and thefact that babies in the control group were of lowerbirth weight.'6'

Inactivation of virus particles within blood productsPrevention of transmitted viral infection (prin-cipally non-A, non-B hepatitis, HIV and hepatitisB) is both time-consuming and relies upon identify-ing donors who carry potentially harmful viruses.Unfortunately such a strategy is not foolproof: forinstance HIV has been transmitted by transfusionwith HIV antibody negative blood on rareoccasions.15 Secondly, other viruses may bepathogenic but occur at such low frequency thatroutine donor testing is not thought to be feasible(e.g. HTLV-I: human T-cell leukaemia lymphomavirus), or their pathogenicity may not yet berecognized. Therefore an alternative strategy toprevent transmission of viral infection by bloodproducts is to inactivate virus within either plasmaand cellular blood products. There are encouragingsigns that photochemical decontamination (PCD)may provide a feasible and effective way of in-activating bacteria and viruses in blood pro-ducts.166'167 Psoralen derivatives are added to theplasma and bind to double-stranded DNA byintercalation, then on exposure to ultra-violet lightthe psoralen derivative covalently binds topyrimidine bases, thereby inhibiting any furthertranscription or replication. This technique is pro-ven to inactivate single or double stranded DNA orRNA viruses.68PCD has been shown to prevent the transmission

of non-A, non-B hepatitis to chimpanzees trans-fused with treated non-A, non-B inocula. Subse-

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HAEMATOLOGY 607

quent challenge with the same inocula, butuntreated, led to classical post-transfusionhepatitis.167 Furthermore, this study was carriedout on plasma which contained factor VIIIcactivity and PCD did not result in a significant fallin this activity.167 A further study has applied asimilar technique to inactivating virus withinplatelet concentrates.169 Other techniques of viralinactivation are also being investigated includingthe use ofgamma irradiation and laser ultra-violetlight.169

New books

The speed of change in medicine coupled with thetime taken for a textbook to come to fruition meansthat far too many are out of date by the time theyarrive in the shops. However, it is worth mention-ing two books published in the last 18 months. Dr

Chanarin has brought out a bench-top guide to allaspects of laboratory haematology. It is an up todate benchtop guide written by over 100 authorsand is authoratative and easy to use. It is a superbbook and at a cost of less than £30, it should bebought by all serious haematology departments.'70The beginning of the 1980s saw a spate of new

editions ofthe major haematology reference tomes,and these are now beginning to show their age.Therefore a new edition of 'Williams' is to bewelcomed: it is 1920 pages long and fromexperience with previous editions it should providea useful reference work for the 1990s.'7'

AcknowledgementsI am especially grateful to Christine Carr for huntingdown all the references and also to Donald Moir andTerry West for their helpful and constructive commentson the draft manuscript

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3. Hambley, H. & Mufit, G.J. Editorial: Erythropoietin: an oldfriend revisited Br Med J 1990, 300: 621-622.

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5. Winearls, C.G., Oliver, D.O., Pippard, M.J., Reid, C.,Downing, M.R. & Cotes, P.M. Effect of recombinanterythropoietin derived from recombinant DNA on theanaemia of patients maintained by chronic haemodialysis.Lancet 1986, ii: 1175-1177.

6. Eschbach, J.W., Egrie, J.C., Downing, M.R., Browne, J.K.& Adamson, J.W. Correction of the anemia of end-stagerenal disease with recombinant human erythropoietin. NEngl J Med 1987, 316: 73-78.

7. Eschbach, J.W., Abdulhadi, M.H., Browne, J.K. et al.Recombinant human erythropoietin in anemic patients withend-stage renal disease. Ann Intern Med 1989, 111:992-1000.

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17. Brandt, S.J., Peter, W.P., Ahoater, S.K. et al. Effect ofrecombinant human granulocyte macrophage colonystimulating factor on hemopoietic reconstitution after highdose chemotherapy and autologous bone marrow trans-plantation. N Engl J Med 1988, 318: 869-875.

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21. Ganser, A., Volkes, B., Greher, J. et al. Recombinant humangranulocyte macrophage colony stimulating factor inpatients with myelodysplastic syndromes - a phase I/II trial.Blood 1989, 73: 31-37.

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44. Editorial. Childhood leukaemia, radiation and the paternalgerm cell. Lancet 1990, i: 447.

45. Cook-Mozaffari, P., Darby, S. & Doll, R. Cancer nearpotential sites of nuclear installations. Lancet 1989, ii:1145-1147.

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47. Muir, K.R., Parkes, S.E., Graham, R. & Mann, J.R.Observations on a cluster of childhood leukaemia in Tel-ford. Br Med J 1990, 300: 676-677.

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50. Kaldor, J.M., Day, N.E., Clarke, E.A. et al. Leukemiafollowing Hodgkin's disease. N EnglJMed 1990,322:7-13.

51. Kaldor, J.M., Day, N.E., Pettersson, F. et al. Leukemiafollowing chemotherapy for ovarian cancer. N Engl J Med1990, 322: 1-6.

52. Jacobs, A. Benzene and leukaemia. Br J Haematol 1989, 72:119-121.

53. Rinsky, R.A., Smith, A.B., Hornung, R. et al. Benzene andleukemia: an epidemiological risk assessment. N Engl J Med1987, 316: 1044-1050.

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55. Le Beau, M.M., Albain, K.S., Larson, R.A. et al. Clinicaland cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlym-phocytic leukemia: further evidence for characteristicabnormalities ofchromosome no 5 and 7. J Clin Oncol 1986,4: 325-345.

56. Fenaux, P., Preudhomme, C., Lai, J.L., Morel, P., Beuscart,R. & Bauters, F. Cytogenetics and their prognostic value inde novo acute myeloid leukaemia: a report of 283 cases. Br JHaematol 1989, 73: 61-67.

57. Schiffer, C.A., Lee, E.J., Tomiyasu, T., Wiemik, P.H. &Testa, J.R. Prognostic impact of cytogenetic abnormalitiesin patients with de novo acute non lymphocytic leukemia.Blood 1989, 73: 263-270.

58. Diaz, M.O., Rubin, C.M., Harden, A. et al. Deletions ofinterferon genes in acute lymphoblastic leukemia. N Engl JMed 1990, 322, 77-82.

Treatment of acute leukaemia59. Hussein, K.K., Dahlberg, S., Head, D. et al. Treatment of

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60. Stiller, C.A. & Draper, G.J. Treatment centre size, entry totrials, and survival in acute lymphoblastic leukaemia. ArchDis Child 1989, 64: 657-661.

61. Rees, J.K.H., Gray, R.G., Swirsky, D. & Hayhoe, F.G.J.Principal results of the Medical Research Council's 8thacute myeloid leukaemia trial. Lancet 1986, ii: 1236-1241.

62. Editorial. Treatment of childhood acute lymphoblasticleukaemia. Lancet 1988, i: 683-685.

63. Mayer, R.J. Allogeneic transplantation versus intensivechemotherapy in first remission acute leukemia: is there a'best choice'? J Clin Oncol 1988, 6: 1532-1536.

64. International Bone Marrow Transplant Registry. Trans-plant or chemotherapy in acute myelogenous leukaemia.Lancet 1989, i: 1119-1122.

65. Editorial. Autologous bone marrow transplantation. Lancet1987, i: 303-304.

66. Gottlieb, D.J., Prentice, H.G., Heslop, H.E. et al. Effects ofrecombinant interleukin-2 administration on cytotoxicfunction following high-dose chemo-radiotherapy forhematological malignancy. Blood 1989, 74: 2335-2342.

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68. Brincker, H. & Christensen, B.E. Long term survival andlate relapses in acute leukaemia in adults. Br J Haematol1990, 74: 156-160.

69. Cheson, B.D., Lacerna, L., Leyland-Jones, B., Sarosy, G. &Wittes, R.E. Autologous bone marrow transplantation. AnnInt Med 1989, 110: 51-65.

70. Gale, R.P. & Butturini, A., Autotransplants in leukaemia.Lancet 1989, ii: 315-318.

71. Okamoto, S., Olson, A.C., Berdel, W.E. & Vogler, W.R.Purging of acute myeloid leukaemic cells by ether lipids andhyperthermia. Blood 1988, 72: 1777-1783.

72. Sullivan, K.M., Storb, R., Buckner, C.D. et al. Graft-versus-host disease as adoptive immunotherapy in patients withadvanced hematologic neoplasms. N Engl J Med 1989, 320:828-833.

73. Horowitz, M.M., Gale, R.P., Barrett, A.J. et al. for Inter-national Bone Marrow Transplant Registry. Effect ofmethotrexate on relapse after bone-marrow transplantationfor acute lymphoblastic leukaemia. Lancet 1989, i: 535-537.

74. Jones, R.J., Vogelsang, G.B., Hess, A.D. et al. Induction ofgraft-versus-host disease after autologous bone marrowtransplantation. Lancet 1989, i: 754-757.

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76. Reiffers, J., Gaspard, M.H., Maraninchi, D. et al. Com-parison ofallogeneic or autologous bone marrow transplan-tation and chemotherapy in patients with acute myeloidleukaemia in first remission: a prospective controlled trial.Br J Haematol 1989, 72: 57-63.

77. Lowenberg, B., Verdonck, L.J., Dekker, A.W. et al.Autologous bone marrow transplantation in acuteleukaemia in first remission: results of a Dutch prospectivestudy. J Clin Oncol 1990, 8: 287-294.

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Aggressive therapy for multiple myeloma79. Barlogie, B., Epstein, J., Selvanayagam, P. & Alexanian, R.

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80. Gore, M.E., Selby, P.J., Viner, C. et al. Intensive treatmentof multiple myeloma and criteria for complete remission.Lancet 1989, ii: 879-882.

81. Samson, D., Gaminara, E., Newland, A. et al. Infusion ofvincristine and doxorubicin with oral dexamethasone asfirst-line therapy for multiple myeloma. Lancet 1989, ii:882-884.

82. Barlogie, B., Smith, L. & Alexanian, R. Effective treatmentof advanced multiple myeloma refractory to alkylatingagents. N Engl J Med 1984, 310: 1353-1356.

83. Lokhorst, H.M., Meuwissen, O.J.A.T., Bast, E.J.E.G. &Dekker, A.W. VAD chemotherapy for refractory multiplemyeloma. Br J Haematol 1989, 71: 25-30.

84. Fermand, J.-P., Levy, Y., Gerota, J. et al. Treatment ofaggressive multiple myeloma by high-dose chemotherapyand total body irradiation followed by blood stem cellsautologous graft. Blood 1989, 73: 20-23.

85. Reiffers, J., Marit, G. & Boiron, J.-M. Peripheral bloodstem-cell transplantation in intensive treatment of multiplemyeloma. Lancet 1989, ii: 1336.

86. Mandelli, F., Tribalto, M., Awisati, G. et al. Recombinantinterferon alfa-2b (INTRON A) as post-induction therapyfor responding multiple myeloma patients. M84 protocol.Cancer Treat Reviews 1988, 15 (Suppl A): 43-48.

87. Hjorth, M., Hellquist, L., Holmberg, E., Magnusson, B.,Rodjer, S. & Westin, J. Initial treatment in multiplemyeloma: no advantage of multidrug chemotherapy overmelphalan-prednisone. Br J Haematol 1990, 74: 185-191.

In utero bone marrow transplantation88. Harrison, M.R., Slotnick, R.N., Cromblehome, T.M., Gol-

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Chronic myeloid leukaemia89. Daley, G.Q., van Etten, R.A. & Baltimore, D. Induction of

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91. Wiedemann, L.M., Karhi, K.K., Shirji, M.K. et al. Thecorrelation of breakpoint cluster region rearrangement andp210 phl/abl expression with morphological analysis ofPh-negative chronic myeloid leukemia and other myelopro-liferative diseases. Blood 1988, 71: 349-355.

92. Bergsagel, D.E. The chronic leukemias: a review of diseasemanifestations and the aims of therapy. Can Med Assoc J1967, 96: 1615-1620.

93. Prischl, F.C., Haas, O.A., Lion, T., Eyb, R. & Schwarz-meier, J.D. Duration of first remission as an indicator oflong-term survival in chronic myelogenous leukaemia. Br JHaematol 1989, 71: 337-342.

94. Sokal, J.E., Baccarini, M., Russo, D. & Tura, S. Staging andprognosis in chronic myelogenous leukemia. Semin Hematol1988, 25: 49-61.

95. Thomas, E.D. & Clift, R.A. Indications for marrow trans-plantation in chronic myelogenous leukemia. Blood 1989,73: 861-864.

96. Goldman, J.M., Gale, R.P., Horowitz, M.M. et al. Bonemarrow transplantation for chronic myelogenous leukemiain chronic phase. Ann Int Med 1988, 108: 806-814.

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98. Gabert, J., Thuret, I., Lafage, M., Carcasonne, Y.,Maraninchi, D. & Mannoni, P. Detection of residual bcr/abltranslocation by polymerase chain reaction in chronicmyeloid leukaemia patients after bone-marrow transplanta-tion. Lancet 1989, ii: 1125-1128.

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100. Freund, M., von Wussow, P., Diedrich, H. et al. Recom-binant human interferon (IFN) alpha-2b in chronicmyelogenous leukaemia: dose dependency of response andfrequency of neutralizing anti-interferon antibodies. Br JHaematol 1989, 72: 350-356.

Essential thrombocythaemia101. Dudley, J.M., Messinezy, M., Erisani, S. et al. Primary

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102. Giles, F.J., Singer, C.R.J., Gray, A.G. et al. Alpha-interferon therapy for essential thrombocythaemia. Lancet1988, ii: 70-72.

103. Gisslinger, H. Ludwig, H., Linkesch, W., Chott, A., Fritz, E.& Radaszkiewicz, T. Long-term interferon therapy forthrombocytosis in myeloproliferative diseases. Lancet 1989,i: 634-636.

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Chronic lymphocytic leukaemia107. Binet, J.-L., Catovsky, D., Chastang, C. et al. Prognostic

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108. Binet, J.L., Catovsky, D., Dighiero, G. et al. Chroniclymphocytic leukemia: recommendations for diagnosis,staging, and response criteria. Ann Int Med 1989, 110:236-238.

109. Binet, J.-L., Chastang, C., Dighiero, G. et al. Long termresults of the CHOP regimen in stage C chronic lymphocyticleukaemia. Br J Haematol 1989, 73: 334-340.

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Cell lineage of Hodgkin's disease111. Jaffe, E.S. The elusive Reed-Sternberg cell. N Engl J Med

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Isolation of Reed-Sternberg cells from lymph nodes ofHodgkin's disease patients. Blood 1989, 73: 222-229.

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115. Dallenbach, F.E. & Stein, H. Expression of T-cell-receptorbeta chain in Reed-Sternberg cells. Lancet 1989, ii: 828-830.

116. Weiss, L.M., Movahed, L.A., Warnke, R.A. & Sklar, J.Detection of Epstein-Barr viral genomes in Reed-Sternbergcells of Hodgkin's disease. N Engl J Med 1989, 320:502-506.

117. Uccini, S., Monardo, F., Ruco, L.P. et al. High frequency ofEpstein-Barr virus genome in HIV-positive patients withHodgkin's disease. Lancet 1989, i: 1458.

Iron chelation therapy118. Zurlo, M.G., De Stefano, P., Borgna-Pignatti, C. et al.

Survival and causes of death in thalassaemia major. Lancet1989, ii: 27-29.

119. Kontoghiorghes, G.J., Aldouri, M.A., Sheppard, L. &Hoffbrand, A.V. 1,2-dimethyl-3-hydroxypyrid-4-one anorally active chelator for treatment of iron overload. Lancet1987, i: 1294-1295.

120. Porter, J.B., Hoyes, A.P., Abeysinghe, R., Huehns, E.R. &Hider, R.C. Animal toxicology of oral iron chelator LI.Lancet 1989, ii: 156.

121. Hoffbrand, A.V., Bartlett, A.N., Veys, P.A., O'Connor,N.T.J. & Kontoghiorghes, G. Agranulocytosis and throm-bocytopenia in patient with Blackfan-Diamond anaemiaduring oral iron chelator trial. Lancet 1989, ii: 457.

122. Alter, B.P. Agranulocytosis and thrombocytopenia, Black-fan Diamond anaemia and oral iron chelation. Lancet 1990,ii: 970.

123. Kontoghiorghes, G.J. & Hoffbrand, A.V. Clinical trials withoral iron chelator LI. Lancet 1989, ii: 1516-1517.

124. Editorial. Oral iron chelators. Lancet 1989, ii: 1016-1017.

Rhesus haemolytic disease of the newborn125. Bowman, J.M., Chown, B., Lewis, M. & Pollock, J.M. Rh

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126. Thornton, J.G., Page, C., Foote, G., Arthur, G.R., Tovey,L.A.D. & Scott, J.S. Efficacy and long term effects ofantenatal prophylaxis with anti-D immunoglobulin. Br MedJ 1989, 298: 1671-1673.

Haemophilia A127. Fletcher, M.L., Trowell, J.M., Craske, J., Pavier, K. &

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128. Brettler, D.B. & Levine, P.H., Factor concentrates fortreatment of hemophilia: which one to choose? Blood 1989,73: 2067-2073.

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Desmopressin130. Mannucci, P.M. Desmopressin: a nontransfusional form of

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131. Mannucci, P.M., Remuzzi, G., Pusineri, F. et al. Deamino-8-D-arginine vasopressin shortens the bleeding time inuremia. N Engl J Med 1983, 308: 8-12.

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Rare causes of thrombocytopenia134. Chong, B.H., Pitney, W.E. & Castaldi, P.A., Heparin

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135. Frame, J.N., Mulvey, K.P., Phares, J.C. & Anderson, M.J.Correction of severe heparin-associated thrombocytopeniawith intravenous immunoglobulin. Ann Int Med 1989, 111:946-947.

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Platelet transfusion therapy138. NIH consensus conference. Platelet transfusion therapy.

JAMA 1987, 257: 1777-1780.139. Editorial. Platelet transfusion therapy. Lancet 1987, ii:

490-491.140. Hutchinson, R.E., Kunkel, K.D., Schell, M.J. et al.

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141. Schiffer, C.A. & Slichter, S.J. Platelet transfusion fromsingle donors. N Engl J Med 1982; 307: 245-247.

Tranexamic acid142. Bartholomew, J.R., Salgia, R. & Bell, W.R. Control of

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143. Hoyle, C.F., Swirsky, D.M., Freedman, L. & Hayhoe,F.G.J. Beneficial effect of heparin the management ofpatients with APL. Br J Haematol 1988, 68: 283-289.

144. Awisati, G., Cate, J.W.T., Buller, H.R. & Mandelli, F.Tranexamic acid for control of haemorrhage in acutepromyelocytic leukaemia. Lancet 1989, ii: 122-124.

145. Sindet-Pedersen, S., Ramstrom, G., Bernvil, S. & Blomback,M. Hemostatic effect of tranexamic acid mouthwash inanticoagulant treated patients undergoing oral surgery. NEngl J Med 1989, 320: 840-843.

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148. Mulder, N.H., Elema, J.D. & Postmus, P.E. Transfusionassociated graft-versus-host disease in autologous bonemarrow transplantation. Lancet 1989, i: 735-736.

Transmission of infection by blood transfusion149. Peterman, T.A., Ward, J.W. What's happening to the

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150. Ward, J.W., Holmberg, S.D., Allen, J.R. et al. Transmissionof human immunodeficiency virus (HIV) by blood trans-fusions screened as negative for HIV antibody. N Engl JMed 1988, 318: 473-478.

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152. Lefrere, J.J. & Girot, R. Risk ofHIV infection in polytrans-fused thalassaemia patients. Lancet 1989, ii: 813.

153. Alter, M.J. Non-A, non-B hepatitis: sorting through adiagnosis of exclusion. Ann Int Med 1989, 110: 583-585.

154. Bradley, D.W. The agents ofnon-A, non-B hepatitis. J VirolMeth 1985, 10: 307-319.

155. Editorial. Will the real hepatitis C stand up? Lancet 1989, ii:307-308.

156. Kuo, G., Choo, Q.L., Alter, H.J. et al. An assay forcirculating antibodies to a major etiologic virus of humannon-A, non-B hepatitis. Science 1989, 244: 362-364.

157. van der Poel, C.L., Reesink, H.W., Lelie, P.N. et al.Anti-hepatitis C antibodies and non-A, non-B post trans-fusion hepatitis in the Netherlands. Lancet 1989, ii:297-299.

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