FrancescoPassamonti,MD, ElisaRumi, MD, EsterPungolino,MD, Lucia Malabarba,MD,
PaolaBertazzoni,MD, Marina Valentini-,MD, EsterOrlandi, MD, LucaArcaini, MD,
ErcoleBrusamolino,MD, CristianaPascutto,PhD, Mario Cazzola,MD, EnricaMorra, MD,
Mario Lazzarino,MD
PURPOSE: To assesslife expectancy and prognostic factors for
survival in patients with polycythemia vera and essential thrombocythemia.
METHODS: The study sample consisted of 831 consecutive
patients with polycythemia vera (n = 396; 4184 person-years of
follow-up) or essential thrombocythemia (n = 435; 4304 person-years of follow-up). Mortality in each group was compared
with the Italian population using the standardized mortality
ratio (SMR) based on life expectancy data obtained from the
Italian Institute of Statistics.
RESULTS: The IS-year survival was 65% in patients with polycythemia and 73% in those with thrombocythemia. By Cox re-
gressionanalysis,the independentpredictors of deathwere a
P
olycythemia
are
chronic
vera
and
myeloproliferative
essential
thrombocythemia
disorders
(1,2).
The
incidence is 2.3 per 100,000 person-years for polycythemia (3) and 2.5 for thrombocythemia (4). Both diseasesfollow a chronic clinical course with increased risk
of thrombosis and of evolution to myelofibrosis with myeloid metaplasia or acute leukemia (5,6). Only few studies
have provided information on life expectancy of patients
with polycythemia vera or essential thrombocythemia
compared with that of the general.population (3,4,7,8).
The study by Rozman and coworkers (7) on 801 patients
did not report a decreasedlife expectancy for polycythemia or thrombocythemia, but this result was not confirmed by subsequent studies with fewer patients but
longer follow-up (3,4,8). In addition, studies comparing
the mortality of patients with that of the general population by means of the standardized mortality ratio (SMR)
yield conflicting results (9-16).
From the Division of Hematology (FP, ER, LM, PB, EO, LA, EB, CP,
MC, ML), IRCCS PoliclinicoSan Matteo, University of Pavia, Pavia,
Italy; and Division of Hematology (EP, MV, EM), Niguarda Ca Granda
Hospital, Milan, Italy.
Requests for reprints should be addressed to Francesco Passamonti,
MD, Division of Hematology, IRCCS Policlinico San Matteo,
University of Pavia, Viale Golgi 19, 27100 Pavia, Italy, or
[email protected].
Manuscript submitted April 26, 2004, and accepted in revised form
June 10,2004.
@ 2004 by Elsevier Inc
All rights reserved.
history of thrombosis for polycythemia (hazard ratio [HR] =
2.2; P = 0.0002) and thrombocythemia (HR = 2; P = 0.01),and
male sex (HR = 1,8; P = 0.03) for thrombocythemia. Mortality
compared with the general population was 1.6-fold higher
(P <0.001) in patients with polycythemia but was not increased
in those with thrombocythemia (SMR = I; P = 0.8).
CONCLUSION: Life expectancy of patients with polycythemia
vera (especially if younger than 50 years) was reduced compared
with the general population, whereas life expectancy of patients
with essentialthrombocythemia was not affected significantly by
the disease,reflecting the more indolent nature of the proliferation.
History of thrombosis was the main predictor of death in both
diseases.Am J Merl. 2004;117:755-761. @2004by ElsevierInc.
We conducted a study aimed at defining life expectancy of 831 consecutive patients with polycythemia
vera or essentialthrombocythemia treated in two Italian hospitals from 1970 to 2002. The two cohorts of
patients werecomparedwith the Italian generalpopulation, taking into account age,sex, and calendar period.
METHODS
Patients
This study included 831 consecutive patients (396 with
polycythemia and 435 with thrombocythemia) diagnosed from January 1970 to June 2002 at the Division of
Hematology of Policlinico San Matteo of Pavia and the
Division of Hematology of the Niguarda Ca Granda Hospital of Milan, two general hospitals in Italy with all medical and surgical specialties. The study was conducted in
accordance with institutional guidelines established for
retrospective studies. All patients were followed at the
same center until September 2003. The diagnostic criteria
were those in use for polycythemia vera (17-19) and for
essential thrombocythemia (20-22) at the time of the
first observation. Diagnosis of acute leukemia was according to French-American-British criteria (23). Diagnosis of myelofibrosis was according to the Italian ConsensusConference criteria (24).
0OO2-9343/04/$-see front matter
doi: IO.IOI6/i.amimed.2004.06.032
755
Life Expectancy and Survival in Patients with Polycythemia Vera and Essential Thrombocythemia/Passamonti et al
Endpoints and Statistical Analysis
Numerical variablesare summarizedasmediansand interquartile ranges.Categoricalvariablesare describedas
count and relativefrequency(%). The primary endpoint
wasto evaluatelife expectancy.Mortality of patientswith
polycythemiaand thrombocythemiawascomparedseparately with the mortality of the Italian population by
meansof the standardizedmortality ratio, which is the
ratio of the observednumber of deathsin the study sample to the number of deathsexpectedaccordingto a setof
referencemortality rates,adjustedfor age,sex,and calendar year. For this purpose,the Italian referenceratesby
sex,5-yearagebands,and singlecalendaryear were obtained from the Istituto Nazionaledi Statistica(1STAT).
A standardizedmortality ratio> 1 meansa higher mortality than expectedin the referencepopulation. P values
and 95% confidenceintervalsfor the standardizedmortality ratio were calculatedby applying a Gaussianapproximation to the log-likelihood (25). To assessthe
changesin standardizedmortality ratio with ageand calendar year at diagnosis,patientswere also grouped according to calendarperiod (before 1990;since1990)and
age«50 years;50 to 64 years;;:=:65
years).Survivalanalysiswasperformed using the Kaplan-Meiermethod. To
comparethe survival of patientswith the life expectancy
of the Italian population, eachpatient was matchedby
sex, age,and calendaryear at diagnosisto a reference
personwhosesurvivalwasthe patient'slife expectancyat
diagnosis,accordingto the life tablesof the Italian population publishedyearlyby ISTAT. Comparisonbetween
the two survivalcurveswasperformedusingthe log-rank
test.
A secondary endpoint was the evaluation of each
event occurring during follow-up. For each event, we
estimated the incidence rate with the corresponding
95% confidenceinterval, calculatedfrom the Gaussian
approximation to the log-likelihood, and the actuarial
risk, calculated from the cumulative probability of
event-free survival (Kaplan-Meier method). To identify prognostic factors for survival, Cox proportional
hazard regressionanalysisincluded the following factors at diagnosis:age,sex,history of thrombo- hemorrhagic events,splenomegaly,hemoglobin level, leukocyte count, and platelet count. The two-tailed Fisher
exacttest was used to compare frequencies.All statistical analyseswere performed using Microsoft Excel
2000 (Redmond, Washington) and Statistica 6.1 (StatSoft Inc., Tulsa, Oklahoma).
At diagnosis,the median agewas 59 yearsfor patients with
polycythemia vera and 55 yearsfor essentialthrombocythemia (Table 1). Patients with polycythemia vera were more
November 15. 2004
Characteristics
and Outcomes of Patients with
Polycythemia Vera
At diagnosis, 227 (57%) of the 396 patients with polycythemia vera had at least one risk factor for thrombosis
(age >60 years or history of vascular events). For 342
patients (86%), the main treatment was myelosuppressive therapy. Phlebotomy was the sole treatment for 54
patients (14%; median time on treatment: 5 years; interquartile range, 8.4 years). Low-dose aspirin was begun at
diagnosis in 226 patients (57%).
As of September 2003, 267 patients (67%) were alive
and 129 (33%) had died, with a median survival of 20
years. The survival of patients with polycythemia was reduced significantly (P = 0.01) compared with the life
expectancy of the Italian population, adjusted for calendar year, sex, and age (Figure I). At 15 years, the survival
for polycythemia vera was 65%, with a cumulative risk of
27% for thrombosis (Table 2). Among baseline characteristics, only a history of thrombosis was an independent
predictor of death (hazard ratio [HR] = 2.2; P <0.001).
Thrombotic complications included myocardial infarction in 8 patients (2%), ischemic stroke in 8 (2%),
transient ischemic attack in 13 (3%), pulmonary embolism in 2 «1%), deep vein thrombosis in 11 (2%), and
superficial thrombophlebitis of the lower limb in 5 (1%).
Myeloid leukemias evolyed directly from polycythemia
after a median of 14 years (interquartile range, 7.3 years)
and myelofibrosis after 13 years (interquartile range, 9.8
years). Three of the 21 patients (14%) with myelofibrosis
due to polycythemia developed acute leukemia.
The incidence of leukemia and myelofibrosis was not significantly different among patients who received various
single-agenttreatments, but combination drug therapy was
associatedwith a significantly higher incidence of acute leukemia compared with pipobroman (P = 0.005) or hydroxyurea (P = 0.04) (Table 3). Solid cancersinvolved the
lung (n = 4 patients), digestivetract (n = 4), femalegenitals
(n = 2), femalebreast(n = 2), bladder (n = 1), and prostate
(n = 1). Two patients developedlymphoproliferative disorders. Of20 patients who developedsolid cancers,16 (80%)
had receivedsingle-agenttherapy.
Patients with polycythemia vera had significantly
higher mortality than the general population (Table 4).
The significantly lower standardized mortality ratios after
1990 was influenced by the significantly (P = 0.05) lower
incidence of acute leukemia and myelofibrosis among patients diagnosed after that time. The incidence of thrombosis was significantly lower (P = 0.01) in patients
RESULTS
756
commonly male (63%), whereaspatientswith essential
thrombocythemiaweremore commonlyfemale(62%).
younger than 65 years (15.3 per 1000 person-years; 95%
confidence interval [CI]: 11.5 to 20.3 per 1000 personyears) than in those over 65 years of age (29.5 per 1000
person-years; 95% CI: 19.2 to 45.3 per 1000 person-
THE AMERICANJOURNAL
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fe Expectancy and Survival in Patients with Polycythe,nia Vera and Essential Thrombocythemia/Passa,nonti et al
Table 1. Characteristicsand Treatment of 831 Patientswith PolycythemiaVera and Essential
Thrombocythemia
PolycythemiaVera
(n = 396)
Characteristic
EssentialThrombocythemia
(n = 435)
-
-
Median [Interquartile Range)or Number (%)
9.6 [11.1)
. 10 (2.5)
4184
59 [19J
251 (63%)
114(29)
Follow-up (years)
Patientslost to follow-up
Person-years
of follow-up
Age (years)
Male sex(0/0)
Vascl,Ilareventsat diagnosis
Treatment
Pipobroman
Time on treatment(years)
Hydroxyurea
Time on treatment (years)
Busulfan
Time on treatment (years)
Combination drug
Time on treatment (years)
9.3 [8.4]
10 (2.3)
4304
SS[29]
163(38%)
84 (19)
194 (56)
10 [11.6]
71 (21)
8.7 [7.9]
26 (8)
9 [8.8]
51 (15)
14.7 [8.5]
years). There was not a significant difference in incidence
of leukemia(P = 0.54) and myelofibrosis(P = 0.60) between age groups.
Characteristics and Outcomes of Patients with
Essential Thrombocythemia
At diagnosis,250patients(57%) with essentialthrombocythemiahad at leastone risk factor for thrombosis(age
>60 years,history of vascularevents,or platelet count
151 (43)
11.9 [10.9]
133 (38)
8.4 [5.9]
34 (10)
12.3 [8.7]
33 (9)
11.1 [10.31
> 1500 X 109fL). A myelosuppressive treatment was used
in 351 patients (81%). The remaining 84 patients (19%;
median time since diagnosis: 8.1 years) were followed
without therapy. Low-dose aspirin was begun at diagnosis in 342 patients (79%).
As of September 2003, 358 (82%) of the 435 patients
with essential thrombocythemia were alive and 77 (18%)
had died, with a median survival of22.6 years.Survival of
patients with essential thrombocythemia was not signifi-
--
Polycythemia vera patients
Reference cohort
p = 001
C>
c
">
"~
:3
U)
C
0
"-e
80
tl:
Q)
>
~
"5
E
:3
U
--'--
45
No. at risk 396
Figure
1. Survival
282
186
104
52
50
55
60
65
8
curves of 396 patients with polycythemia
vera compared
November IS, 2004
with life expectancy of the general population
THE AMERICANJOURNAL
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757
Lift Expectancyand Survival in Patients with Polycythemia Vera and Essential ThrombocythemialPassamonti et al
Polycythemia
= 396)*
Vera (n
EssentialThrombocythemia
(n = 435)t
Percentage,
Incidenceper 1000Person-years
(95% ConfidenceInterval), or Number (%)
IS-yearoverall survival (%)
Incidence
Thrombosis
Leukemia
Myelofibrosis
Solid cancer
IS-yearcumulativerisk (%)
Thrombosis
Leukemia
Myelofibrosis
Solid cancer
Causeof death
Thrombosis
Hemorrhage
Leukemia
Myelofibrosis
Solid cancer
Not relatedto polycythemiavera
and essentialthrombocythemia§
Unknown
73
65
17.9 (14.1--22.7)
5.3 (3.5- 8)
5.1 (3.3- 7.8)
5.8 (3.9- 8.7)
11.6 (8.7-15.5)
1.2 (0.5-2.8)
1.6 (0.8-3.4)
4 (2.5-6.4)
27
7
6
9
(n1=129)
261(20)
31(2)
251(19)*
11(9)
161(12)
351(28)
13(10)
.
17
2
4
8
(n
= 77)
20(2.6)
1 (1)
6 (8)*
3 (4)
11 (14)
31 (40)
5 (7)
4184 person-years of follow-up.
t 4303 person-years of follow-up.
* Including leukemia, or postrnyelofibrotic evolution of polycythemia vera or essential thrombocythemia.
S Includes degenerative diseasesof the nervous system, cardiomyopathy, chronic liver diseases,renal failure,
and trauma.
cantlydifferent (P = 0.39) from the life expectancy of the
general population, adjusted for calendar year, sex, and
age (Figure 2). The IS-year survival of patients with essential thrombocythemia was 73%, with a cumulative
17% risk of thrombosis (Table 2). Among baseline characteristics, male sex (HR ==1.8; P = 0.03) and a history of
thrombosis (HR = 2; P = 0.01) were independent predictors of mortality.
Thrombotic complications included myocardial infarction in 8 patients (2%), angina pectoris in 3 (.<1%),
ischemic stroke in 9 (2%), transient ischemic attack in 13
(3%), pulmonary embolism in 4 (1%), peripheral arteriopathy in 4 (1%), deep vein thrombosis in 9 (2%), and
superficial thrombophlebitis of the lower limb in 18
(4%). Myeloid leukemias evolved directly from essential
thrombocythemia after a median of 14.5 years (inter-
Table 3. Incidence of Acute Leukemia and Myelofibrosis among Patients with Polycythemia Vera and Essential Thrombocythemia,
by Type of Treatment Received
EssentialThrombocythemia(n
Treatment
Acute Leukemia
Myelofibrosis
Acute Leukemia
= 435)
Myelofibrosis
IncidenceX 1000Person-years(95% ConfidenceInterval)
Pipobroman
Hydroxyurea
Busulfan
Combination drug
Phlebotomy
No cytoredl!ction
4.2 (2.2-8.1)*
3.2 (0.8-12.8)*
3.4 (0.5-24.4)
14.1 (7.6-26.1)
0
1.9 (0.7-5)*
6.5 (2.4-17.2)
6.9 (1.7-27.7)
12.8(6.7-24.7)
5 (1.3-20)
1.2(0.3-4.7)
1.7(0.4-6.7)
0
3.2 (0.5-23)
1.2(0.3-4.7)
1.7(0.4-6.7)
0
6.5 (1.6-26)
0
1.4 (0.2-9.8)
Incidence was significantly lower (P <0.05) compared with the incidence in patients receiving combination drug therapy.
Sequential use of two or more myelosuppressive agents.
758
November IS, 2004
THE AMERICANJOURNAL
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Life Expectancy and Survival in Patients with Polycythemia Vera and Essential ThrombocythemialPassamonti
Polycythemia Vera (n
Standardized
Mortality Ratio
(95% Confidence
lntervai)
No.of
Deaths!
No.of
Patients
Person-years
of Follow-up
129/396
4184
1.6
104/129
25/129
2925
1259
0.9 (0.6-1.4)
29/130
53/150
47/116
1733
1649
802
.3:-1.9)*
1.9 (1.6-2.3)"
quartile range, 8.1 years), whereas myelofibrosis occurred
at a median of 10.9 years (interquartile range, 3.9 years).
One of the 7 patients (14%) with myelofibrosis due to
thrombocythemia developed acute leukemia. The incidence of acute leukemia and myelofibrosis did not differ
significantly among treatments (Table 3). Solid cancers
involved the lung (n = 3 patients), digestive tract (n = 3),
female breast (n = 3), prostate (n = I), and brain (n = 1).
Two patients developed non-Hodgkin lymphoma. Of 15
patients who developed solid cancers, 14 (93%) had received single-agent therapy.
No. of
Deaths/
No. of
Patients
Standardized
Mortality Ratio
(95% Confidence
Interval)
77/435
4304
(o.s-
44/134
33/301
2044
2260
1.2(0.9- .6)
0.9 (0.6- .3)
2036
1237
1031
.4 (0.6-3.2)
1 (0.6-1.5)
1 (0.8-1.3)
The mortality of patients with essentialthrombocythemia wasnot significantly higher than the generalpopulation
(Table 4).
of Disease-Related Complications
in Polycythemia and Thrombocythemia
Patientswith polycythemiahad a significantlyhigher incidence of thrombosis (P = 0.001),leukemia(P = 0.02),
and myelofibrosis(P = 0.006) comparedwith patients
with essentialthrombocythemia,but both groupshad a
Comparison
similar risk of solid cancers (P = 0.23; Table 2). The ther-
--
1.0 ~-
Essential thrombocythemia
Reference cohort
patients
P = 039
.
30
~
5
10
15
20
.
35
~
--'--
40
45
50
55
60
65
Time (years)
No. at risk: 435 328 200
80
26
2
Figure 2. Survival curvesof 435 patients with essentialthrombocythemiacomparedwith life expectancyof the generalpopula.
tion.
November 15,2004
THE AMERICANJOURNAL
OFMEDICJN~
VohJm~
Life Expectancy
and Survival in Patients with Polycythemia Vera and Essential ThrombocythemialPassamonti et al
apy-adjusted hazard ratios for polycythemia versus
thrombocythemia were 1.6 for thrombosis (P = 0.Q1),
3.6for acuteleukemia(P = 0.01),and 2.9for myelofibrosis (P = 0.02). The hazard ratios for solid cancerswere
not significantly different betweenpatientswith polycythemia and thrombocythemia{HR = 1.4;P = 0.32).
DISCUSSION
Studies providing clinical information on the life expectancy of patients With polycythemia vera or essential
thrombocythemia compared With the general population
are limited (3,4,7,8). In one often quoted study (7), the
life expectancy of patients With polycythemia vera or essential thrombocythemia was not different from that of
the general population. The relatively short follow-up of
the sample, however, may have masked late complications that affect life expectancy, such as leukemia or myelofibrosis (12,14). Studies With a longer follow-up, but
with a small number of patients, have reported a shortened life expectancy in patients With polycythemia (3) or
thrombocythemia (4,8).
In the present study of 831 consecutive patients With
polycythemia vera or essential thrombocythemia followed for a median of 9.5 years, the cause of death was
known for 94% of patients. The surviyal rate at 15 years
for both groups of patients confirms the long-lasting nature of the two diseases(9-14,25-29). In our study, the
standardized mortality ratio was 1.6-fold higher for patients With polycythemia vera in comparison with the
general population, whereas the ratio for patients With
essentialthrombocythemia was no different than the general population.
The more favorable mortality ratios for patients With
polycythemia vera diagnosed after 1990 did not depend
on changing clinical features at presentation or on treatment, but rather was related to a lower incidence of late
complications. The mortality ratio for patients With essential thrombocythemia, on the contrary, remained unchanged over time.
Younger patients With polycythemia had standardized
mortality ratios that were significantly higher than 1. Since
thrombosis is more likely in older patients, the excessof
mortality in younger patients may be relatedto the relatively
.higher occurrence of acute leukemia. Becauseof the longlasting nature of polycythemia vera, younger agemay allow
more time for a natural evolution into acute leukemia to
occur. The more prolonged exposureof younger patients to
myelosuppressivedrugs may also playa role.
Our finding that the survival of patients With polycythemia vera was significantly lower than the life expectancy of the general population differs from Rozman's
study (7). This discrepancy may be explained by our
longer follow-up, which highlights the negative effect of
760
November 15.2004
late vascular events and of late hematologic complications such asacute leukemia or myelofibrosis. Our results
are in keeping with those obtained by Ania et al (3) in a
limited number of patients followed for a long time.
By comparison, our study shows that life expectancy
was not reduced by essential thrombocythemia, presumably because of its more benign nature. The higher medIan ageand the high prevalence of thrombosis in a prior
study (8) may explain why it has been reported otherwise.
We found that a history of thrombosis adversely affected survival of patients with polycythemia vera and
essential thrombocythemia. For both diseases,thrombosis remains the most frequent complication during follow-up and the main causeof death. The higher incidence
of thrombosis in patients with polycythemia vera than in
those with essential thrombocythemia suggeststhat caution should be exercised when considering polycythemia
and thrombocythemia as diseaseswith a comparable risk
of thrombosis, and emphasizes the beneficial role of aspirin in polycythemia vera (30). The finding of a better
survival for women than men with essential thrombocythemia is in part a reflection of a better survival for
women in the general population as well as a slightly
higher incidence of leukemia (31) and arterial thrombosis (32) in men.
In this study, the risk of transformation to acute leukemia in patients with polycythemia vera or essential
thrombocythemia was relatively low (IS-year risk of 7%
and 2%). This low IS-year cumulative risk of leukemia
will make it very difficult to design a study to compare the
leukemogenic potential of different cytoreductive agents
in the two diseases.
The designof the present study doesnot permit definitive
conclusions regarding the associationbetweentype of treatment and the risk of transformation to either acuteleukemia
or myelofibrosis. It is notable, however, that patients who
receivedonly phlebotomy did not developleukemia,but the
number of patients was too small and the follow-up too
short to draw definitive conclusions. No statisticallysignificant differencesin the incidence of leukemia were found in
each diseasebetween patients treated with hydroxyurea or
with pipobroman. On the contrary, the sequential use of
different myelosuppressivedrugs, which usually implies resistant disease,was associatedwith a higher risk ofleukemia
transformation compared with patients who receiveda single agent.
The different risk of leukemia and myelofibrosis in patients with polycythemia vera compared with essential
thrombocythemia, even after accounting for type of
treatment, indicates that the two diseaseshave different
propensities to leukemic transformation. The risk of evolution to myelofibrosis in patients with polycythemia
vera and essential thrombocythemia (IS-year risk of 6%
and 4%) parallels that of leukemia. Although this study
was not a controlled trial, the incidence of myelofibrosis
THE AMERICANJOURNAL
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Life Expectancy and Surviva/.in Patients with Polycythemia Vera and Essential ThrombocythemialPassamonti et al
in polycythemia vera appeared particularly low in patients who received pipobroman, a result similar to that
of a randomized trial comparing hydroxyurea with pipobroman (11).
In conclusion, the prolong~d follow-up of this study
gives a reliable estimate of life expectancy of patients with
polycythemia vera and essential thrombocythemia. Both
diseasesare chronic disorders, with median survivals ex:'
ceeding 20 years. The main complication is thrombosis,
especially in polycythemia vera, thereby implying that an
assessmentof risk f~ctors for thrombosis should be included in the evaluation of all patients with polycythemia
vera and essential thrombocythemia. Modifications of
risk-increasing lifestyles should be advised. Leukemia
may occur in both diseases,but with a low incidence.
Overall, life expectancy of patients with polycythemia
vera, especially in patients younger than 50 years old, is
reduced when compared with the general population. On
the contrary, life expectancy of patients with essential
thrombocythemia is not markedly affected by the disease,
reflecting the more indolent nature of the proliferation.
ACKNOWLEDGMENT
This studywassupportedin part by a grant from the Associazione Italiana per la RicercasuI Cancro(AIRC, ResearchProject
entitled "Genomicanalysisof hematopoieticcellsin myelodysplastic syndromesand myeloproliferativedisorders"), Milan,
Italy.
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