Cancer Medicine

Open Access

ORIGINAL RESEARCH

Noninvasive early detection of anthracycline-­induced
cardiotoxicity in patients with hematologic malignancies
using the phased tracking method
Yoshiko Saito1,2, Ikuko Susukida2, Yoshiro Uzuka2 & Hiroshi Kanai3
1Department of Food and Nutrition, Miyagigakuin Women’s University, Sendai, Japan
2Sendai Blood Disease Center, Sendai, Japan
3Graduate School of Biomedical Engineering and the Graduate School of Engineering, Tohoku University, Sendai, Japan

Keywords
Acute leukemia, anthracycline, cardiotoxicity,
echocardiography, malignant lymphoma,
phased tracking method
Correspondence
Yoshiko Saito, Department of Food andNutrition, Miyagi Women’s University, D241
9-1-1 Sakuragaoka Aobaku, Sendai city,
Miyagi Prefecture, Japan.
Tel: (81)22 279 1311; Fax: (81)22 244 5755;
E-mails: sy33814@topaz.ocn.ne.jp,
ysaitou@mgu.ac.jp
Hiroshi Kanai, Engineering and the Graduate
School of Engineering, Tohoku University,
Sendai, Japan; 6-6-05 Aza Aoba Aramaki
Aobaku, Sendai city, Miyagi Prefecture,
Japan. Tel: (81)22 795 5800; Fax: (81)22 795
5801; E-mail: kanai@ecei.tohoku.ac.jp
Funding Information
This study was supported by the Sendai Blood
Disease Center SBDC and no specific funding
was disclosed.
Received: 3 April 2016; Revised: 24 May
2016; Accepted: 3 June 2016
Cancer Medicine 2016; 5(9):2276–2285
doi: 10.1002/cam4.813

Abstract
Anthracyclines are among the most effective and widely used anticancer drugs;
however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We
evaluated cardiac function in 142 patients using conventional echocardiography
and the phased tracking method (PTM), which was measured using the minutevibration and the rapid motion components, neither of which is recognized instandard M-­mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional
echocardiography with the average velocity of ventricular septum myocytes (Vave)in the PTM. The Vave of 12 healthy volunteers was 1.5 (m/s)/m or more. At
baseline of 99 patients, there was a positive correlation between LVEF and Vavein all patients. There were no significant differences in baseline cardiac function
between patients with and without HF. There was a negative correlation between
the cumulative anthracycline dose and LVEF or Vave among all patients. We
determined that Vave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m
to 55%, and 1.0 (m/s)/m to 50%. During the follow-­up period, there was apathological decrease in LVEF (<55%) and Vave (<1.25 m/s/m) in patients with
HF; decreases in Vave were detected significantly earlier than those in LVEF
(P < 0.001). When Vave declined to 1.5 (m/s)/m or less, careful continuous
observation and cardiac examination was required. When Vave further declined
to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus,
serious drug-­induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate-­term monitoring of left ventricle systolic function associatedwith anthracycline chemotherapy, among patients with hematologic malignancies.
The PTM was an effective laboratory procedure to avoid the progression toserious cardiomyopathy.

Introduction
Anthracycline treatment significantly improves the survivalof patients with cancer, but can result in serious cardiotoxicity; therefore, effective monitoring of anthracycline-­
induced changes in cardiac function could detect changes
early enough to implement treatment strategies to significantly reduce or prevent such life-­
threatening
2276

complications [1]. The development of noninvasive, reproducible, easy-­to-­use, sensitive diagnostic techniques would
greatly improve the detection of early pathological changes
associated with treatment regimens [2, 3]. One such technique is the phased tracking method (PTM) [4], a high-­
resolution Doppler measurement that is useful for detecting
cardiac transmural changes [5, 6], the PTM is measured
on minute amplitude on the order of several tens of© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.

Detection of Drug-­Induced Cardiotoxicity

Y. Saito et al.

micrometers up to several hundred Hertz, which has neither been recognized in TDI nor standard M-­
mode,
B-­mode, 2D-­strain echocardiography. These fine measurement characteristics and the rapid minute amplitude haveallowed measurement of the fetal heart and the fetal
descending aorta of normal and growth-­restricted fetuses[7, 8].
The aim of this study was to compare changes in left
ventricle cardiac parameters detected using the PTM withthose obtained using conventional echocardiography inorder to evaluate whether the PTM is superior for thedetection of early anthracycline-­induced changes in cardiac
function in patients with acute lymphocytic leukemia(ALL), acute myeloid leukemia (AML), and malignant
lymphoma (ML). We had experienced a case on the basisof the PTM measurement data, by adjusting the chemotherapy schedule as the development of serious cardiomyopathy was prevented [9] and improvement of prognosis
is expected.

Chemotherapeutic protocols
Patients with ALL or ML underwent the modified CHOP
protocol [10, 11], whereas those with AML underwent
therapy with daunorubicin and cytosine-­arabinoside [12–14]. Daunorubicin doses were converted to doxorubicin
equivalents using a conversion factor of 0.56 that was
the proposed equivalent tumor effect doses obtained witha standard protocol.

Echocardiography
Patients underwent comprehensive two-­dimensional andDoppler echocardiographic examinations, which were performed by a single doctor using a EUB 655 ultrasoundscanner (Hitachi, Ibaraki, Japan) and a SSD-­500SV ultrasound scanner (ALOKA, Tokyo, Japan) in accordance withrecognized standards. Left ventricular ejection fraction(LVEF) was calculated using modified Teichholz.

Phased tracking method

Methods
Study population
Twelve healthy volunteers and 142 patients with hematologic malignancies were eligible for the PTM and conventional echocardiography. Between August 1998 andAugust 2014, 128 consecutive patients underwent echocardiography and PTM to evaluate cardiac function. An
additional 14 AML patients were examined after completion of chemotherapy in 2009. Patients were grouped
according to the absence or presence of clinical heart
failure (HF), no HF group and HF group, respectively(Table 1). Informed consent was obtained from all
patients.

The ultrasound scanner was switched to the phased tracking mode. By referring to the M-­mode image, which wasconstructed from the analog/digital (A/D) converted data,
we manually preset two points, in the heart wall, between
which, the ultrasonic beam was directed, as illustrated in
Figure 1A. The principles of the PTM are illustrated in
Figure 1B–D. Using the M-­mode PTM as the parasternal
long-­axis view, we measured the M-­mode image, electrocardiography, phonocardiogram, and small-­amplitude
velocity signals of less than a few micrometers of theinterventricular septum (IVS) by tracking the results ofthe multiple points that normalized the speed of the change
in thickness. Because the results obtained by the proposed
method depend on the angle between the direction of

Table 1. Characteristics of patients who underwent echocardiography (n = 142).
No HF group (n = 118)

Number of patients
Male
FemaleAge at diagnosis, years
Average
MedianRange
Current age*, years
Average
MedianRange

HF group (n = 24)

No. pt.

ALL

ML

AML

No. pt.

ALL

ML

AML

No. pt

142
72
70

13
4
9

20
14
6

85
43
42

61
57

1
0
1

13
7
6

10
4
6

11
13

58
62
16–89

51.5
51
18–82

50.6
48
18–80

54.7
58
14–88

21
/
/

56.8
55
41–74

47.8
54
18–69

53
54
14–86

53
50
18–82

56.6
57
20–84

62.7
66
15–93

27
/
/

64
60
46–87

54.2
56
21–79

HF, heart failure; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; ML, malignant lymphoma, *, Final inspection age.

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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Detection of Drug-­Induced Cardiotoxicity

Y. Saito et al.

Figure 1. Process of the evaluation of the local change in the thickness during one cardiac cycle.

Figure 2. Formula to calculate the average velocity (Vave) of cardiomyocytes in the interventricular septum during opening and closing of the aortic
valve.

the velocity vector and the ultrasonic beam, the directionof the ultrasonic beam passing through heart wall was
selected, so that the beam was almost perpendicular toeach wall during the A/D conversion of several cardiac

2278

cycles. During the acquisition period, respiration was suspended. Figure 2 shows the superimposed estimates ofthe velocity signals {v -­ (xi; t)} of each heart beat on the
tracked points {xi -­ (t)} on IVS during six heartbeats.
© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Detection of Drug-­Induced Cardiotoxicity

Y. Saito et al.

The vertical axis of these figures was inverted so that thenegative value of the velocity, which is shown above thebaseline, corresponds to the situation in which the object
moves in the direction of the ultrasonic transducer on
the chest wall. The resultant velocity signals are sufficiently
reproducible for six heartbeat periods. The results wereimmediately visualized and output as shown in Figure 2.

Statistical analyses
The results are presented by the mean and median values.
Paired and nonpaired two-­tailed Student’s t-­tests were used
to compare parameters between the groups using the
JMP11 statistical software (SAS Institute Inc., Cary, NC).

Results
The contractile force and contraction synchrony of myocardial cells was measured using the PTM. We analyzed
the period between aortic valve opening and closing (asshown in Fig. 3) and calculated the average velocity (Vave)
using the following equation:
where Vmax is the highest velocity of the layers.
f2
n2
∑
∑

Δh =

evaluations are shown in Table 1. Patients were divided
into two groups; no clinical cardiac symptoms (no HF
group and cardiac clinical symptoms HF group). HF
occurred in 11 male patients and 13 female patients,
respectively (odds ratio 0.79 95% CI: 0.33–1.91). There
were no significant differences between patient characteristics in the ALL, AML, and ML groups, with the exceptionof the mean age of patients with ALL, which was 21 years
at the time of diagnosis, approximately 30 years younger
than the average age of patients in the other groups.
Prior to treatment, baseline LVEF was positively correlated with Vave (r = 0.7468; Fig. 4). One hundred andeighteen patients had no clinical HF, with a maximum
anthracycline dose of 2205 mg/m2. Among the 24 patientsin HF group, the minimum cumulative anthracycline
dose associated with development of HF was 241 mg/
m2. There were no significant differences in baseline
cardiac function between no HF group and HF group(Table 2).

Δh(n;m)m=f1 n=n1(f2 − f1 )(n2 − n1 )Of the 142 patients who underwent echocardiographic
evaluations, 128 patients were sequentially examined during and after the completion of chemotherapy; however,patients sometimes missed examinations for deconditioning.
Fourteen patients were evaluated only once, ten or more
years long after completion of chemotherapy. Characteristicsof the 142 patients who underwent echocardiographic

Figure 4. Correlation with left ventricular ejection fraction and averagevelocity at baseline.

Figure 3. Average velocity of change in thickness for determination.

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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Table 2. Baseline cardiac functions between patients with no clinicalcardiac symptoms (no heart failure [HF] Group) and those with congestive heart failure clinical symptoms (HF Group).

Echocardiography
CTR %QTC, sec
IVC, mm
AO, mm
LA mm
LVEF
FS
PEP/ET
A/E
The PTM
Vave (m/s)/m
Ths/thd
Vmax (m/s)/m

No HF group
Mean
average ± SD

HF group
Mean
average ± SD

P

47 ± 0.06
0.42 ± 0.039
11.12 ± 2.86
19.64 ± 3.1430 ± 5.09
0.753 ± 0.063
0.374 ± 0.055
0.253 ± 0.119
0.884 ± 0.272

46.3 ± 0.04
0.4225 ± 0.026
10.7 ± 1.85
19.7 ± 2.21
29.7 ± 3.52
0.76 ± 6.6
0.378 ± 5.4
0.31 ± 0.082
0.84 ± 0.386

0.5
0.6
0.62
0.64
0.52
0.84
0.06
0.96
0.7

2.427 ± 0.971
2.14 ± 071
21.89 ± 17.64

2.39 ± 0.972
2.06 ± 0.676
24.7 ± 17.64

0.94
0.82
0.09

AO, aortic valve diameter; CTR, cardiothoracic ratio; E/A, left ventricular
flow; FS, fractional shortening; IVC, inferior vena cava diameter; LA, left
atrial diameter; LVEF, left ventricular ejection fraction; PEP/ET, pre-­ejection time/ejection time; PTM, phased tracking method; QTc, correction QT time; SD, standard deviation; Ths/Thd, ratio of thickness in thesystolic and in the diastolic phase; Vave, average velocity of cardiomyocytes; Vmax, maximum velocity of cardiomyocytes.

Table 3 shows the correlation between the cumulative
anthracycline dose and LVEF or Vave. Both LVEF andVave decreased with increasing anthracycline cumulative
dose in all patients. However, in HF group, Vave decreased
at a significantly smaller cumulative dose point than
did LVEF (P = 0.003). Vave also significantly decreased
2–3 years after the completion of chemotherapy(P = 0.01); however, among patients who survived morethan 5 years after the completion of chemotherapy,
those in no HF group had recovered cardiac function,

whereas cardiac function remained depressed in HF
group. In no HF group, LVEF was not shown the
reduction but Vave showed decreased (0.001), also, in
HF group, Vave was shown a significant declined than
LVEF (0.01) after completion of chemotherapy.
In accordance with the historical proposal of cardiotoxicity definition [14, 15], Vave 1.5 (m/s)/m was comparable
to LVEF 60%, Vave 1.25 (m/s)/m to LVEF 55%, and Vave
1.0 (m/s)/m to LVEF 50%, at 1 and 12 months before
the onset of HF [2, 16] (Fig. 4). As shown in Table 4,
Vave declined significantly earlier than did LVEF. Figure
5 shows the correlation between %LVEF and Vave during
the courses of chemotherapy. The value of the linear slope
in Fig. 5 (r = 0.6) was lower than that in Fig. 4 (r =0.74). The effect of myocardial disturbance on chemotherapy
was more sensitive in terms of the Vave than the LVEF.
In Table 5, among 12 healthy volunteers, 99 patients
before chemotherapy with no heart disease at baseline,
and 26 patients with hematologic disease with neither
malignancy nor heart disease, the average value of Vavewas 2.503 (m/s)/m, with maximum and minimum valuesof 5.117 (m/s)/m and 0.99 (m/s)/m, respectively).
10% had Vave ≤ 1.5 (m/s)/m and 2.5% had Vave ≤ 1.0(m/s)/m (Fig. 6A). Figure 6B shows the values of Vavein 520 examinations during the course of the study. Among
this group, 20 of 49 patients (40.8%) with Vave ≤ 1.0(m/s)/m developed HF, and 14 of these patients with
Vave ≤ 0.5 (m/s)/m soon developed severe HF.
Table 6 shows data regarding the sensitivity and specificity of Vave. Powerful and effective action of the heartis sustained by synchronization of cardiac myocytes. In
Figure 2B, the mottled pattern of a visualized color-­coded
velocity signal schematic shows disturbance of the continuous smooth movement at the left ventricular septum,
during opening and closing of the aortic valve. Cut-­offvalue setting of faster velocity is needed further study.

Table 3. Correlation between the cumulative anthracycline dose and the cardiac functions of left ventricular ejection fraction and average velocity ofcardiomyocytes.
No heart failure (HF) group

HF group

Cumulative DOX
Dose (mg/m2)

LVEF (%)
Mean ± SD

Vave ((m/s)/m)
Mean ± SDn

LVEF (%)
Mean ± SD

Vave((m/s)/m)
Mean ± SD

n

0
100
200
300
400
500
600
Completion of CT after 2–3yCompletion of CT after 5or more years

75.3 ± 6.3
74 ± 5.9
74.7 ± 6.2
73.5 ± 5.3
73 ± 5.7
68.8 ± 6.4
71 ± 1.1
71 ± 10.99
71 ± 9.2

2.43 ± 0.97
2.075 ± 0.904
2.14 ± 0.853
2.008 ± 0.637
2.13 ± 0.665
2.157 ± 0.775
2.2 ± 0.086
1.82 ± 0.805
1.99 ± 0.82

87
42
46
46
44
46
41
45
50

76 ± 673.1 ± 5.1
71.3 ± 6.9
68.8 ± 6.8
68.8 ± 9.9
66.5 ± 8.2
61.8 ± 13.6
54 ± 13.9
50.9 ± 13.9

2.43 ± 0.97
1.851 ± 0.749
2.080 ± 0.815
1.879 ± 0.676
1.89 ± 0.924
1.75 ± 0.459
1.32 ± 0.64
1.096 ± 0.805
0.95 ± 1.016

18
14
16
17
18
15
17
13
10

CT, chemotherapy; DOX, doxorubicin; SD, standard deviation; LVEF, left ventricular ejection fraction; Vave, average velocity of cardiomyocytes.

2280© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Detection of Drug-­Induced Cardiotoxicity

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Table 4. Percentile incidence of left ventricular ejection fraction and average velocity of cardiomyocytes from 1 to 12 months before the onset ofcongestive heart failure (HF).
Period of up to the onset ofcongestive HF

1 monthbefore2 months
before3 months
before6 months
before12 months
beforeP-­value

LVEF < 60%
Vave < 1.5 (m/s)/m
LVEF < 55%
Vave < 1.25 (m/s)/m
LVEF < 50%
Vave < 1.0 (m/s)/m

46.2
73
23
64
23
45.5

60
62.5
40
62.5
20
62.5

40
80
20
70
20
40

54.5
60
20
60
19
40

9
50
9
50
9
20

0.048
0.01
0.01

LVEF, left ventricular ejection fraction; Vave, average velocity of cardiomyocytes.
Table 5. Average and maximum velocity of cardiomyocytes and the ejection fraction at baseline, among healthy volunteers and patients.

Healthy volunteers

Baseline

Nonmalignant hematologic diseases

Total cases

LVEF
Vave
Vmax
LVEF
Vave
Vmax
LVEF
Vave
Vmax
LVEF
Vave
Vmax

No of examined cases

Average

Mean

Range

SD

12

0.71
2.49
25.27
0.76
2.46
22.22
0.78
2.429
18.888
0.75
2.482
22.19

0.72
2.28
21.45
0.76
2.25
19.4
0.76
2.2
20.01
0.76
2.252
19.7

0.6–0.81
1.75–12.33
12.33–40.18
0.76–0.88
0.54–5.1
5–43.1
0.86–0.53
5.84–1.2
9–35
0.52–0.88
0.99–5.835
5.8–76

0.076
0.96
9.5
0.063
0.915
12.8130.08
1.154
14.1950.07
0.953
12.778

99

26

137

LVEF, left ventricular ejection fraction; Vave, average velocity of cardiomyocytes; Vmax, maximum velocity of cardiomyocytes.

Figure 5. Correlation between the percentage left ventricular ejection
fraction (%LVEF) and average velocity of ventricular septum myocytes(Vave) during the course of chemotherapy.

Table 6. The determination of sensitivity and specificity for the detection of congestive heart failure by the Vave with the phased tracking
method.
Vave (m/s)/m

Sensitivity

Specificity

1.25
1
0.5

0.98
0.87
0.64

0.96
0.96
1

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

When Vave values fell to ≤1.5 (m/s)/m, the rest period
was extended to allow recovery of at least Vave 1.5 (m/s)/m,then the following treatment was initiated. For cases inwhich Vave decreased <1.0 (m/s)/m, we canceled additional
chemotherapy treatment. Even if myocardial damage isexpressed, it is possible to long-­term survival if not experienced recurrence (P = 0.0001) in Table 7. Among patients
who experienced recurrence, cardiac function decreased
and patients developed fatal cardiomyopathy; however,patients who did not relapse did not suffer fatal cardiomyopathy, and some of them recovered [9].
The summary of the aforementioned results and our proposal for clinical treatment of patients in each group areshown in Table 8. Examples of the color-coded image foreach grade of velocity in table 8 are shown in Figure 7.

Discussion
Anthracyclines were originally introduced in the late 1960s
as chemotherapeutic agents. They are extremely effective
drugs for the treatment of leukemia and a wide variety
of solid tumors. In patients undergoing anthracycline
therapy, dose-­dependent myocardial impairment has been
described in 23–74% of cases, with a high incidence of2281

Detection of Drug-­Induced Cardiotoxicity

Y. Saito et al.

Table 7. Survival of patients after Vave decreased below 1.0 (m/s)/m led to the cessation of chemotherapy versus the survival of relapse-­free or­relapsed patients.
Case
NumberSurvival time after cessation of chemotherapy

Survival time after relapse

Average

Mean

Range

Average

Mean

Range

52 months+–163 months +1 months–88 months

–

–

–

4 months

2 months

7 days–17 months

Relapse-­free patients6

131 months+

158 months +Relapsed patients18

24 months
P < 0.0001

17 months

Table 8. The summary of the aforementioned results and our proposal
for clinical treatment.
Vave(m/s)/mCardiotoxicity

Medical care attitude

Grade 0
Grade 1

≧1.5
>1.5–≧1.0

No
Slightly

Grade 2

<1.0–≧0.5

Moderate

Grade 3

<0.5

SevereNo
Careful observation isrequiredTreatment postponed or
discontinuation is desirable.
Fatal cardiomyopathy istight.

HF or fatal complications in 5–19% of cases [2, 3, 17–21].
In contrast, there are no evidence-­
based guidelines formonitoring cardiotoxicity in adult patients with cancer[22, 23]. Currently, echocardiography and multigatedradionuclide angiography are the most commonly usedtechniques for noninvasive baseline and serial assessmentof LVEF [3, 19, 23, 24]. Current echocardiography

guidelines focus on quantitative measurements of LVEF,
rather than visual assessment [2, 17–19, 22, 25–27]. The
fundamentals, strengths, and limitations of these techniques
were the topic of a recently published consensus statement[28, 29]. The high-­
resolution Doppler measurement,
showed the systolic heterogeneity of subendocardial myocardial ischemia in normal subjects [1].
The PTM, which was employed in this study, has been
applied to clinical studies by many researchers, that is,noninvasive evaluation of the myocardial property of contraction and relaxation [5, 30, 31], elasticity of the arterial
wall [32–36], and fatal cardiac or artery [7, 8, 37]. Although
in this study, we reported only Vave during systolic timeat the left ventricular septum, we hypothesize that thedevelopment of more detailed myocardial damaging process
becomes clear by analyzing the continuous temporal relationship with Vave, Vmax, and color image. The natureof cardiac tissue that exhibits low levels of antioxidative
enzymes, such as superoxide dismutase and catalase, makeit more susceptible to redox oxidative stress (ROS)

Figure 6. The values of Vave. (A) The average value of Vave of 12 healthy volunteers and 99 patients before chemotherapy was 2.503 (m/s)/m, withmaximum and minimum values of 5.117 (m/s)/m and 0.99 (m/s)/m, respectively. (B) The average values of Vave in 520 examinations during the courseof the study was 2.012 (m/s)/m, 1.0 (m/s)/m or less in 20 patients, 0.5(m/s)/m or less was 14 patients.

2282© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Detection of Drug-­Induced Cardiotoxicity

Y. Saito et al.

Figure 7. Color-­coded velocity signals to correspond with the Grade; upper the right chamber side, down in the left chamber side, showed thethickness change in the transition rate and the ventricular septal wall of one beat of the heart muscle.

generation and accumulation of oxidative stress. The majormechanism of chemotherapy-­
induced cardiotoxicity
involves the generation of ROS. In turn, elevated ROS
causes cellular damage and alternation responses [38].
Therefore, measurement with noninvasive the PTM, whichis measured with small-­amplitude velocity signals of lessthan a few micrometers, before and after chemotherapy
helps to prevent cardiotoxicity.
Careful observation is required to detect decreases ofmore than 1.0 (m/s)/m in such patients to consider treatment delay or cancelation in order to avoid lethal cardiotoxicity. To circumvent the development of HF, early
detection of drug-­induced changes in cardiac function isessential for preventive intervention. Careful surveillanceusing the PTM could ensure early detection and timely
management of such cardiotoxicity.

Conclusion
The PTM was superior to echocardiography for early,
noninvasive detection and intermediate-­term monitoringof left ventricle systolic function associated with anthracycline chemotherapy in patients with hematologic© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

malignancies. We found that the PTM is a valid laboratory procedure that may help avoid progression to serious
cardiomyopathy.

Acknowledgments
We thank the contribution to retired associate Professor
Yoshiro Koiwa (Tohoku University) and Professor Hideyuki
Hasegawa (Toyama University, GSSEE).

Conflict of Interest
The authors declare no conflicts of interest.
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