Do body composition
parameters correlate with
response to targeted therapy in
ER+/HER2- metastatic breast
cancer patients? Role of
sarcopenia and obesity
Endi Kripa*, Veronica Rizzo, Francesca Galati, Giuliana Moffa,
Federica Cicciarelli, Carlo Catalano and Federica Pediconi
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome,
Purpose: To investigate the association between body composition
parameters, sarcopenia, obesity and prognosis in patients with metastatic
ER+/HER2- breast cancer under therapy with cyclin-dependent kinase
(CDK) 4/6 inhibitors.
Methods: 92 patients with biopsy-proven metastatic ER+/HER2- breast
cancer, treated with CDK 4/6 inhibitors between 2018 and 2021 at our
center, were included in this retrospective analysis. Visceral Adipose Tissue
(VAT), Subcutaneous Adipose Tissue (SAT) and Skeletal Muscle Index (SMI) were
measured before starting therapy with CDK 4/6 inhibitors (Palbociclib,
Abemaciclib or Ribociclib). Measurements were performed on a computed
tomography-derived abdominal image at third lumbar vertebra (L3) level by an
automatic dedicated software (Quantib body composition®,Rotterdam,
Netherlands). Visceral obesity was deﬁned as a VAT area > 130 cm
Sarcopenia was deﬁned as SMI < 40 cm
. Changes in breast lesion size
were evaluated after 6 months of treatment. Response to therapy was assessed
according to RECIST 1.1 criteria. Spearman’s correlation and c
Results: Out of 92 patients, 30 were included in the evaluation. Of the 30
patients (mean age 53 ± 12 years), 7 patients were sarcopenic, 16 were obese,
while 7 patients were neither sarcopenic nor obese. Statistical analyses showed
that good response to therapy was correlated to higher SMI values (p < 0.001),
higher VAT values (p = 0.008) and obesity (p = 0.007); poor response to therapy
was correlated to sarcopenia (p < 0.001). Moreover, there was a signiﬁcant
association between sarcopenia and menopause (p = 0.021) and between
sarcopenia and the persistence of axillary lymphadenopathies after treatment
(p = 0.003), while the disappearance of axillary lymphadenopathies was
associated with obesity (p = 0.028).
Frontiers in Oncology frontiersin.org01
University of Italian Switzerland,
Rubina Manuela Trimboli,
IRCCS San Donato Polyclinic, Italy
Mitera Hospital, Greece
This article was submitted to
Cancer Imaging and
a section of the journal
Frontiers in Oncology
RECEIVED 05 July 2022
ACCEPTED 31 August 2022
PUBLISHED 23 September 2022
Kripa E, Rizzo V, Galati F, Moffa G,
Cicciarelli F, Catalano C and
Pediconi F (2022) Do body
correlate with response to targeted
therapy in ER+/HER2- metastatic
breast cancer patients? Role of
sarcopenia and obesity.
Front. Oncol. 12:987012.
© 2022 Kripa, Rizzo, Galati, Moffa,
Cicciarelli, Catalano and Pediconi. This is
an open-access article distributed under
the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the
original publication in this journal is
cited, in accordance with accepted
academic practice. No use,
distribution or reproduction is
permitted which does not comply with
TYPE Original Research
PUBLISHED 23 September 2022
Conclusions: There is a growing interest in body composition, especially in the
ﬁeld of breast cancer. Our results showed an interesting correlation between
sarcopenia and progression of disease, and demonstrated that VAT can
positively inﬂuence the response to targeted therapy with CDK 4/6 inhibitors.
Larger-scale studies are needed to conﬁrm these preliminary results.
Clinical Relevance: Sarcopenia and obesity seem to predict negative
outcomes in many oncologic entities. Their prevalence and impact in current
breast cancer care are promising but still controversial.
body composition, sarcopenia, obesity, metastatic breast cancer, CDK 4/6 inhibitors,
automatic segmentation, computed-tomography, visceral adipose tissue
Breast cancer (BC) is the most commonly occurring cancer
and the leading cause of cancer death, in women worldwide (1,
2). Nowadays, BC is a complex and heterogeneous disease,
which includes several histological subtypes (3).
Therefore, histological and immunohistochemical
examination of the biopsy or surgical samples of malignant
breast lesions detected on ultrasound, mammography or
magnetic resonance imaging (MRI), is fundamental for
diagnosis, characterization and treatment choice (4). BC has
ﬁve recognized molecular subtypes, primarily deﬁned by the
presence or the absence of hormone receptors (HR), as
summarized in Table 1 (5).
To date, BC therapy is decided in a multidisciplinary setting.
The Eighth Edition of the AJCC classiﬁcation, currently in use,
takes into account the anatomical extension of BC, in terms of
local and systemic extent of disease, and a prognostic
classiﬁcation (Prognostic Stage Group) which includes tumor
grade, HR status, and HER2 status. Therapy involves the
combination of neoadjuvant therapy (in locally advanced and
inoperable BC), surgery, radiotherapy and adjuvant
chemotherapy and/or endocrine therapy (6–9).
There has been an important evolution in therapeutic
strategies through the years, due to the identiﬁcation of
additional prognostic and predictive factors. Among these,
recently body composition parameters, in particular muscle
mass and adipose tissue distribution, have been identiﬁed as
interesting prognostic markers (10). There is a growing interest
in the role of body composition in BC management, as it has
been suggested that it can inﬂuence the response to therapy and
the progression of disease (11,12).
The aim of our study was to evaluate whether sarcopenia and
obesity could predict the response to therapy in patients with
metastatic ER+/HER2- BC, treated with CDK 4/6 inhibitors.
The term sarcopenia indicates a reduction in muscle
strength and mass (13). Obesity is deﬁned as a body mass
index (BMI) of ≥30 kg/m
(14). However, several studies have
shown that BMI alone is not a sufﬁcient and accurate parameter
to assess obesity and to evaluate outcomes and prognosis in
cancer patients, especially when compared with the degree of
visceral obesity (15–17), since BMI lacks in distinguishing
between fat and lean mass and between visceral and
subcutaneous adipose tissue. As known, visceral fat is more
metabolically active than subcutaneous one, and leads to chronic
inﬂammation and tumorigenesis (18).
The ER+/HER2−BC subtype is commonly treated using
hormone-based therapies in the adjuvant setting, with
signiﬁcant survival beneﬁt associated with these therapies even
in the metastatic setting (19). However, hormone resistance
develops in most metastatic patients (20,21). For this reason,
the current standard of care for most patients with ER-positive
metastatic BC consists in CDK 4/6 inhibitors as ﬁrst-line
therapy, in association with aromatase inhibitors or combined
with Fulvestrant, as second-line therapy (22,23). CDK 4/6 are
cell cycle regulators that control the rate of growth and division
TABLE 1 Breast cancer molecular subtypes.
Subtype ER PR HER2 Ki-67
Luminal A-like + ≥20% –< 20%
+ -/< 20%* –≥20%*
HER2-positive –– +
Triple-negative –– –
ER, Estrogen Receptor; PR, Progesterone Receptor.
*Only one of these criteria must be met.
Kripa et al. 10.3389/fonc.2022.987012
Frontiers in Oncology frontiersin.org02
of cells and check important metabolic processes (24,25). In
metastatic BC, these proteins can become overactive, causing
uncontrollable cell growth and division. CDK 4/6 inhibitors
suppress CDK 4/6 proteins, blocking the transition from the G1
to the S phase of the cell cycle, in order to slow down or even to
stop cancer cells replication. Furthermore, recent preclinical
studies have identiﬁed potential targets for diet-induced
obesity in CDK 4 and 6, suggesting that the use of CDK 4/6
inhibitors could have a direct effect on body fat mass and muscle
mass (26,27). Finally, in recent years, muscle and adipose tissue
measurements have received increasing attention as potential
prognostic factors as well as predictors of treatment-related
toxicity (28,29). Thus, the ultimate aim of our research was to
investigate if the amount of adipose tissue, skeletal muscle mass,
obesity and sarcopenia are predictive of a positive or negative
prognosis in metastatic ER+/HER2- BC patients.
Materials and methods
Our research is a retrospective study on patients with a
diagnosis of metastatic ER+/HER2- BC, treated with CDK 4/
The study was performed according to the Declaration of
Helsinki and approved by the Institutional ethics committee.
Written informed consent was waived because of the
retrospective design of this study.
Between November 2018 and November 2021, 92 patients
with metastatic ER+/HER- BC treated with CDK 4/6 inhibitors
combined with endocrine therapy were included in the analysis.
Inclusion criteria were: female gender, age between 18 and
85 years, biopsy-proven (ultrasound-guided or stereotactic)
metastatic ER+/HER2- invasive BC, availability of computed
tomography (CT) images and breast MRI examination at
baseline and after 6 months of treatment.
Patients unsuitable for treatment with CDK 4/6 inhibitors,
previously treated with tamoxifen, aromatase inhibitors or
neoadjuvant chemotherapy (within 30 days prior to
enrollment), previously treated with radiotherapy or ablative
therapy of the affected breast, pregnant, breastfeeding or in
postnatal period, and patients who had any contraindication
to perform CT and/or MRI examinations, were excluded.
Staging multiphasic CT was performed by using a
multidetector CT scanner (Somatom Sensation 64; Siemens
Healthineers, Erlangen, Germany). CT scan was performed
using a ﬁxed tube voltage of 120 kVp, with automatic
exposure control, and an image slice thickness of 1–5 mm. CT
scan protocol included a non contrast phase, followed by a late
arterial phase and a portal venous phase acquisition.
Body composition was quantitatively assessed using an
automatic segmentation software named Quantib body
composition®(Rotterdam, Netherlands) (30,31). Quantib®
evaluated the patient CT-derived image extracted from staging
CT examinations (non-contrast or portal venous phase series) in
our institutional picture archiving and communication system
(PACS). The software performs an automatic segmentation at
the level of L3 vertebral body to calculate subcutaneous adipose
tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle
area (SMA). Lastly, the software automatically generates a form
containing the values of interest, as in Figure 1.
Skeletal Muscle Index (SMI) was then calculated as the ratio
of SMA to the patient’s squared height. According to literature, a
VAT area > 130 cm
indicates obesity and a SMI value < 40 cm
is considered a cut-off value for sarcopenia (32,33).
Therefore, patients were divided into normal weighted, obese,
non-sarcopenic and sarcopenic, accordingly.
All patients also underwent a ﬁrst MRI examination at
baseline, for loco-regional staging, and at least a second MRI
examination 6 months after the beginning of targeted therapy, to
evaluate the change in size of the target lesion during therapy. All
breast MRI were performed on a 3T magnet (Discovery MR 750;
GE Healthcare, Chicago, IL, USA) with a dedicated 8-channel
breast coil compatible with parallel imaging, and patients in a
prone position. Breast MRI protocol included: axial pre-contrast
2D FSE T2-weighted fat-suppressed sequence (repetition time
[RT] = 9000–11,000 ms, echo time [ET] 119–120 ms, matrix =
512 × 224, slice thickness = 3–5 mm, ﬁeld of view [FOV] = 35 ×
35 cm, NEX = 1, scan time = 130 s), axial pre-contrast diffusion-
weighted echo-planar imaging (DWI-EPI) sequence (RT =
4983–5314 ms, ET = 58 ms, matrix = 150 × 150, slice
thickness = 3–5 mm, FOV = 350 × 350 mm, NEX = 2–2–4,
scan time = 230 s), axial dynamic three-dimensional (3D)
spoiled gradient-echo T1-weighted fat-suppressed sequences
(ﬂip angle = 15°, RT = 8 ms, ET = 4 ms, matrix = 512 × 256,
slice thickness = 1.40 mm, FOV = 380 × 380 mm, NEX = 1) and
sagittal 3D spoiled gradient-echo post-contrast T1-
After 6 months of therapy, a re-stadiation CT and MRI were
performed to evaluate distant metastases and local
RECIST 1.1 criteria (34) were used to identify and classify
the response to therapy. A Complete Response (CR) was deﬁned
by the disappearance of all target lesions and the reduction in
short axis to < 10 mm of any pathological lymph nodes; Partial
Response (PR), in case of at least a 30% decrease in the sum of
diameters of target lesions; Progressive Disease (PD), in case of
Kripa et al. 10.3389/fonc.2022.987012
Frontiers in Oncology frontiersin.org03
at least a 20% increase in the sum of diameters of target lesions
and an absolute increase of at least 5 mm; Stable Disease (SD), in
all other cases.
After 6 months of CDK 4/6 inhibitors therapy, we
considered CR and PR as good response to therapy, while PD
and SD as poor response.
Statistical analysis was performed using IBM®SPSS
Statistics, version 25. The Kolmogorov-Smirnov Z test was
performed to assess the normality of the distribution for all
continuous variables. A Spearman’s analysis was carried out to
verify the correlation between variables. A comparison of
categorical variables was performed using the c
P-values < 0.05 were considered statistically signiﬁcant.
From the 92 patients included in the analysis, 6 patients
discontinued therapy due to the onset of toxic side effects; 14
patients could not perform or complete CT or MRI examinations
because of allergy to contrast media or claustrophobia; 33
patients had incomplete CT or MRI imaging sets; 8 patients
waived the follow-up; 1 patient died for other causes. Thus, 30
patients were suitable for the evaluation.
Of the 30 patients (mean age of 53 ± 12 years) with
metastatic ER+/HER2- BC included in the study and treated
Screenshot generated by the software after performing an automatic segmentation at the level of the third lumbar vertebra and report of the
measurements of SAT, VAT and SMA carried out. SAT values are indicated in red and VAT values in green. SMA is obtained by summing the areas of
the psoas, the abdominal and the long spinal muscles indicated in blue, orange and pink respectively (13.1 + 60.1 + 42.5 = 115.7 cm
). SMI is then
calculated as the ratio of SMA to the height squared of the patients.
Kripa et al. 10.3389/fonc.2022.987012
Frontiers in Oncology frontiersin.org04
with CDK 4/6 inhibitors, 19 patients (63.3%) were in menopause
while 11 (36.7%) were not. Obesity was present in 16 patients
(53.3%), normal weight in 14 (46.7%) and sarcopenia in 7
patients (23.3%). None of the patients were both sarcopenic
All patients had axillary lymph node metastases at baseline
local staging MRI and CT. For what concerns distant metastases,
12 patients (40.0%) had liver metastases, 13 patients (43.3%) had
skeletal metastases, 1 (3.3%) patient had lung metastases, and 4
patients (13.3%) had both bone and brain metastases. There
were no differences regarding sites of metastases between
sarcopenic and non-sarcopenic patients and between obese
and normal weighted patients.
Correlation of baseline body
composition parameters and
response to therapy
After 6 months of therapy, 4 patients (13.3%) had PD. All 4
patients had an increase in target lesion’s size of at least 20% and
2 of them had new metastases on 6-month follow-up CT scan. 4
patients showed SD (13.3%). 22 (73.3%) patients had CR or PR
The Kolmogorov-Smirnov Z test demonstrated a non-
normal distribution in the lesions size, both before and after
therapy; the test showed a normal distribution of the variables
SAT, VAT, SMA and SMI.
The median of lesions size assessed before and after
chemotherapy is respectively 25,5 cm (5 - 100 cm) and 13,5
cm (0 - 58 cm).
At CT-scan analysis, BC patients showed a mean VAT of
(SD 62.39), SAT of 213 cm
(SD 89.73), SMA of 128
(SD 33.51) and SMI of 49.75 cm
Spearman’s analysis demonstrated a statistically signiﬁcant
correlation between higher VAT values and a good response to
therapy (p = 0.008) and also between higher SMI values and a
good response to therapy (p < 0.001). Furthermore, a direct
correlation was found between VAT and SMI values (p = 0.04).
Further details are included in Table 2.
analysis showed a statistically signiﬁcant association
between sarcopenia and the persistence (no detectable
modiﬁcations in terms of size and morphology at MRI) of
axillary lymphadenopathies after therapy (p = 0.003), between
sarcopenia and menopause (p = 0.021) and between sarcopenia
and a worse response to therapy (p < 0.001). c
also found that
obesity was associated with a good response to therapy (p =
0.007) and with the absence of axillary lymphadenopathies after
therapy (p = 0.028). No signiﬁcant association was found
between obesity and menopause (Table 3).
In recent years, there is a growing interest in the role of body
composition parameters, sarcopenia and obesity status in several
oncologic entities, including BC, colorectal cancer (35), prostate
cancer (36) and leukemia (37).
It has been established that BMI cannot be sufﬁciently
accurate as a stand-alone parameter to assess body
composition (10,33). An alternative method commonly used
to quantify body composition is dual X-ray absorptiometry
(DEXA), characterized by a relatively low radiation exposure,
low costs and the ability to evaluate the whole body in a single
scan. A further imaging modality in addition to DEXA is CT,
that is able to provide details on speciﬁc muscles, visceral and
subcutaneous adipose tissue while performing a whole body
staging or follow-up in cancer patients. Moreover, CT combines
clinical accessibility with high accuracy in the quantiﬁcation of
speciﬁc tissues and in the evaluation of body composition (38).
In patients with metastatic BC undergoing endocrine
therapy alone, the relationship between BMI and response to
therapy is still controversial. In particular, Zewenghiel et al. have
described no differences in treatment efﬁcacy between normal,
TABLE 2 Statistical correlation between response to therapy and body composition parameters.
Spearman's Rho Response to therapy SAT VAT SMA SMI L3
Response to therapy Correlation coefﬁcient 1.000 0.100 0.476 0.643 0.687
p-value 0.600 0.008 < 0.001 < 0.001
SAT Correlation coefﬁcient 0.100 1.000 0.507 0.051 0.049
p-value 0.600 0.004 0.787 0.799
VAT Correlation coefﬁcient 0.476 0.507 1.000 0.413 0.376
p-value 0.008 0.004 0.023 0.040
SMA Correlation coefﬁcient 0.643 0.051 0.413 1.000 0.937
p-value < 0.001 0.787 0.023 < 0.001
SMI Correlation coefﬁcient 0.687 0.049 0.376 0.937 1.000
p-value < 0.001 0.799 0.040 < 0.001
Statistically signiﬁcant results are bolded (p-value <0.05).
Kripa et al. 10.3389/fonc.2022.987012
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overweight and obese patients with metastatic BC treated with
Fulvestrant (39). On the contrary, Gevorgyan has reported a
worse response in obese patients treated with Fulvestrant (40).
Focusing on VAT, in agreement with Franzoi et al. (40), our
results have shown a correlation between the absolute value of
VAT and the response to therapy with CDK 4/6 inhibitors. This
indicates thata higher VAT value, and therefore the state of
obesity, can predict a better response to treatment (Figure 2). We
supposed that better outcomes of our patients with higher VAT
could be due to the increased expression of CDK 4/6, since CDK
4/6 play an important role in adipogenesis (24). It has been
demonstrated that CDK 4 inﬂuences adipocyte differentiation
and function through the activation of peroxisome proliferator-
activated receptor gamma (PPARg) and that the disruption of
CDK 4 or the presence of activating mutations in CDK 4 in
primary mouse embryonic ﬁbroblasts result in reduced and
increased adipogenic potential of these cells, respectively (41).
Nevertheless, Pizzuti et al. have shown a negative impact of
obesity in terms of Progression Free Survival (PFS) in patients
with endocrine resistant metastatic BC treated with Fulvestrant
(42). Their results, apparently in contrast with ours, could
depend on the different therapeutic line studied or on the
assessment of the state of obesity based on BMI and not on
VAT values. On the contrary, Franzoi et al. (43) have shown that
patients with high visceral fat index had a longer PFS compared
to patients with low visceral fat index.
Regarding low muscle mass and response to treatment,
recently many authors have investigated the role of sarcopenia
TABLE 3 Association between sarcopenia and obesity and clinical
test Sarcopenia (7/30) Obesity (16/30)
Yes 7/7 10/16
No 0/7 6/16
p-value 0.021 0.92
Response to therapy
Good response 0/7 15/16
Poor response 7/7 1/16
p-value <0.001 0.007
Lymphadenopathies after treatment
Presence 7/7 5/16
Absence 0/7 11/16
p-value 0.003 0.028
Statistically signiﬁcant results are bolded (p-value <0.05).
Breast MRI of a 53-year-old obese woman (VAT = 152.8 cm
; VAT > 130 cm
= visceral obesity) with a multifocal breast cancer of the right
breast. Axial post-contrast T1-weighted images before (A) and after (B) 6 months of CDK 4/6 inhibitors show a good response to treatment, as
documented by the reduction in size of all lesions in the upper-outer quadrant/axillary extension of the right breast.
Kripa et al. 10.3389/fonc.2022.987012
Frontiers in Oncology frontiersin.org06
in several oncologic entities, included BC, both in terms of
response to therapy and in relation to toxic side effects associated
with chemotherapy, suggesting that low muscle mass in cancer
patients is an important prognostic factor in terms of treatment-
induced toxicity and survival (44,45).
Our study has shown that sarcopenia could be a negative
prognostic factor in patients with metastatic ER+/HER2- BC
treated with CDK 4/6 inhibitors (Figure 3), in accordance with
the aforementioned recent study by Franzoi (43). Our analysis
has also conﬁrmed that CT is an important diagnostic tool in the
evaluation of sarcopenia and adiposity, in agreement with a
previous study by Cruz-Jentoft (46). Caan et al. also measured
sarcopenia by CT among 3241 patients and has reported an
increased risk of death in patients with early BC presenting this
condition (33). On the contrary, Rier et al. (47) have shown that
low muscle density was associated with worse overall survival
(OS) or PFS in metastatic BC patients treated with 1st-line FAC
(Fluorouracil, Doxorubicin and Cyclophosphamide) or
Paclitaxel, unlike sarcopenia. Prado et al. have reported
sarcopenia as a determinant factor for higher chemotherapy-
related toxicity and shorter time to tumor progression in 55
metastatic BC patients treated with Capecitabine after Taxane
and/or Anthracycline progression (28).
A further notable ﬁnding was the signiﬁcant correlation
between sarcopenia and menopause. This could be explained by
the drop in estradiol levels in menopause. As demonstrated by
Geraci et al. (48), estradiol is an important factor related to the
development of sarcopenia, as it can promote muscle
regeneration, contributing to its health, and is also involved in
the modulation of the local and systemic inﬂammatory
Statistical analysis revealed a direct correlation between VAT
and SMI values. To our knowledge, this ﬁnding is not supported
by other studies in the literature. The result could be occasional
and without clinical relevance. Further studies with a larger
population could conﬁrm or reject our conclusion.
Our study has some limitations. It is a retrospective,
monocentric analysis with a limited number of patients. Even
if our work concerns ER+/HER2- BC treated with CDK 4/6
inhibitors, it would be interesting to evaluate how body
composition affects other BC subtypes and therapeutic lines.
The main originality of our study is due to the dedicated
software we used (Quantib body composition®), which
automatically segments VAT, SAT and SMA on CT images.
The use of a full-automated segmentation software presents
numerous advantages. First, the lack of bias for manual
segmentation, such as the visual determination of the different
anatomical compartments. Furthermore, the automatic
detection of the soma of L3 avoids centering errors. Finally,
the image analysis time is drastically reduced. Another strength
of our study is the local staging performed with breast MRI,
which is the most sensitive imaging modality in terms of BC
detection and assessment of tumor size (51), providing accurate
information on tumor extent, skin and nipple invasion, and
Our study conﬁrms and corroborates the role of sarcopenia
as a potential early predictor of poor prognosis in metastatic BC
patients treated with CDK 4/6 inhibitors. Furthermore, this
Breast MRI of a 57-year-old sarcopenic woman (SMI = 34.3 cm
; SMI < 40 cm
= sarcopenia) with invasive ductal carcinoma of the left
breast. Sagittal post-contrast T1-weighted images, before (A) and after (B) 6 months of treatment shows a substantial stability in the size of the
lesion located in the lower-outer quadrant of the left breast.
Kripa et al. 10.3389/fonc.2022.987012
Frontiers in Oncology frontiersin.org07
study highlights the value of VAT measurement as a more
accurate indicator of obesity than BMI and demonstrates that
an increase in VAT could be associated with a better prognosis
in metastatic ER+/HER2- BC patients. Further large-scale
studies are needed to validate the predictive role of sarcopenia
and VAT during CDK 4/6 inhibition.
Data availability statement
The raw data supporting the conclusions of this article will
be made available by the authors, without undue reservation.
Conceptualization: EK, VR and FG; Material preparation,
data collection and analysis: EK, VR, FC. Writing: EK, GM.
Supervision: VR, GM, and FG. Validation: FG, CC, FP. All
authors contributed to the article and approved the
Conﬂict of interest
The authors declare that the research was conducted in the
absence of any commercial or ﬁnancial relationships that could
be construed as a potential conﬂict of interest.
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their afﬁliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
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