Rasmussen College Lymphoblastic Leukemia Treatment Research Paper Treatment options for acute and chronic diseases continue to advance in efforts to cure d

Rasmussen College Lymphoblastic Leukemia Treatment Research Paper Treatment options for acute and chronic diseases continue to advance in efforts to cure diseases or manage symptoms and improve quality of life. While working in healthcare, it is important to be able to research treatment options to understand the different treatments or questions patients may need to consider.

Select 1 disease directly related to one of the body systems reviewed in this module. Research and select a peer reviewed article written within the past 5 years discussing treatment options for the selected disease and write a 1-page (minimum) Annotated Bibliography. For annotated bibliographies, use standard APA format for the citations, then add a brief entry, including:

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1 or 2 sentences to assess and evaluate the source including if this information is reliable and discuss if the source is objective or biased.
1 or 2 sentences to reflect on the source including how this information can benefit a patient and your understanding of the selected disease.

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Endothelial Function in Children with Acute Lymphoblastic Leukemia (ALL) May Reflect the Clinical Outcome.

Academic Journal

By: Doroszko, Adrian; Niedzielska, Ewa; Jakubowski, Maciej; Porwolik, Julita; Turek-Jakubowska, Aleksandra; Szahidewicz-Krupska, Ewa; Sieczkowski, Bartosz; Dobrowolski, Piotr; Radziwon, Aneta; Skomro, Robert; Derkacz, Arkadiusz; Mazur, Grzegorz; Chybicka, Alicja; Szuba, Andrzej. BioMed Research International. 11/11/2018, p1-8. 8p. DOI: 10.1155/2018/7918091. , Database: EBSCO MegaFILE

Subjects: EPITHELIAL cells — Physiology; LYMPHOBLASTIC leukemia treatment; LYMPHOBLASTIC leukemia prognosis; LYMPHOBLASTIC leukemia diagnosis; BLOOD coagulation factors; CELL adhesion molecules; VASCULAR endothelial growth factors; TREATMENTeffectiveness

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BioMed Research International
Volume 2018, Article ID 7918091, 8 pages
https://doi.org/10.1155/2018/7918091
Research Article
Endothelial Function in Children with Acute Lymphoblastic
Leukemia (ALL) May Reflect the Clinical Outcome
Adrian Doroszko ,1 Ewa Niedzielska,2 Maciej Jakubowski ,1 Julita Porwolik,2
Aleksandra Turek-Jakubowska,1 Ewa Szahidewicz-Krupska ,1 Bartosz Sieczkowski,3
Piotr Dobrowolski,4 Aneta Radziwon,5 Robert Skomro ,6 Arkadiusz Derkacz ,1
Grzegorz Mazur,1 Alicja Chybicka,2 and Andrzej Szuba 7
1
Department of Internal Medicine, Hypertension and Clinical Oncology, Faculty of Medicine, Wroclaw Medical University,
213 Borowska St., Wroclaw, 50-556, Poland
2
Department of Pediatric Oncology, Hematology and Bone Marrow Transplantation, Wroclaw Medical University,
213 Borowska St., Wroclaw, 50-556, Poland
3
Clinic of Neurology, Regional Hospital, Rzeszów, Poland
4
Department of Congenital Heart Diseases, Institute of Cardiology, Warsaw, Poland
5
Glostrup Research Institute, Glostrup, Denmark
6
Division of Respiratory and Critical Care Medicine, Department of Medicine, University of Saskatchewan, Saskatoon, Canada
7
Division of Angiology, Faculty of Health Science, Wroclaw Medical University, 5 Bartla St., Wroclaw, 51-618, Poland
Correspondence should be addressed to Adrian Doroszko; adrian.doroszko@umed.wroc.pl
Received 11 July 2018; Accepted 8 October 2018; Published 11 November 2018
Guest Editor: Agata Stanek
Copyright © 2018 Adrian Doroszko et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Endothelial dysfunction is a common feature of early complications of hemato-oncologic therapy. The aim of our study was to
assess the profile of endothelial function at diagnosis time, then during initial treatment phase of acute lymphoblastic leukemia
(ALL), and to verify the presence of its correlation with early clinical outcome (ECO). 28 ALL children and 18 healthy age-matched
control ones were recruited. Study group was examined at baseline and at 33rd and 78th day of treatment. At each protocol step
the endothelial function was assessed by measurement of sP-selectin (CD62-P), PAI-1(serpinE1), sE-selectin (CD62E), sICAM1(sCD54), sVCAM-1(sCD106), and VEGF concentrations. Higher baseline sICAM-1 and sVCAM-1 levels and lower sP-selectin and
VEGF were observed in children with ALL. sICAM-1, sVCAM-1, and sE-selectin levels were decreasing following the treatment
with protocol I. Higher sE-selectin and lower baseline sICAM-1 levels were observed in children treated unsuccessfully. Lower PAI1 levels were observed in children who survived. Higher baseline sE-selectin levels and lower sICAM-1 and VEGF were observed
in children treated unsuccessfully. A decrease in sE-selectin and lower PAI-1 at the 78th day of therapy were associated with better
ECO. High baseline VEGF and sE-selectin levels, significant increase in PAI-1, and low initial sICAM-1 levels are prognostics for
poorer prognosis in the ALL children.
1. Introduction
Activation of vascular endothelium under pathological conditions is associated with an increased risk of death in
numerous severe diseases [1–4]. Endothelial dysfunction
(ED) is a common feature of many early complications of
hemato-oncologic therapy which remain significant cause of
morbidity and mortality despite the continuous optimization
of treatment protocols [5]. Furthermore, their pathogenesis
remains poorly understood.
Up to date, there are some established determinants
of the endothelial cell injury development, but in a vast
majority they are connected with chemotherapeutics (especially calcineurin inhibitors), methods used for conditioning (cytostatic, total body irradiation (TBI)), and certain
aspects of the bone marrow transplant procedure itself
2
[6]. However, direct risk stratification associated with the
present treatment is difficult due to the complexity and
multiplicity of interactions, which can in different ways and
magnitude generate dysfunction and structural damage to
the endothelium. In our previous publication we showed
that endothelial dysfunction belongs to pathologies observed
in childhood ALL prior to treatment and it may result
from increased plasma concentration of ADMA (asymmetric
dimethylarginine). Additionally, at 78th day of treatment
we observed both improvement in endothelial function and
reduction of plasma ADMA concentration. Interestingly,
it was accompanied by reduction of plasma prostacyclin
concentration [7]. Recognizing endothelial dysfunction as a
multifactorial disease, we intended to broaden in this paper
the spectrum of analyses.
Under physiological condition there is a continuous
balance in an interplay between chemokines acting proand antiaggregatory (such as PAI-1, sE-selectin, sP-selectin)
as well as pro- and anti-inflammatory (i.e., TxB2, 6-ketoPGF-1, sVCAM-1, sICAM-1) leading to the maintenance of
vascular homeostasis and determining appropriate endothelial function [8]. Furthermore, the critical localization of
endothelial cells between streaming blood and remaining
components of vascular wall places them in a pathophysiological mainstream of cardiovascular consequences of
hemato-oncological malignances.
ALL is an aggressive disease characterized by accumulation of immature malignant cells and the risk for relapse
varies between patients and depends not only on genetic
abnormalities, but also on growth factors action. An inverse
relationship between blast proliferation and the magnitude of
response to growth factors has been observed [9]. Furthermore, there are some reports stating that there are increased
levels of soluble intercellular adhesion molecule-1 (sICAM1) [10], soluble vascular cell adhesion molecule-1 (sVCAM-1),
soluble E-selectin [11], thrombomodulin, and von Willebrand
factor [12] in ALL children at the time of diagnosis, which
indicates that ED may be present before the treatment begins.
To summarize, in this study we intended to clarify
these relationships and verify the usefulness of analyzing
selected markers of endothelial dysfunction for early risk
stratification, as well as the ability to monitor the severity of
complications. Hence, the aim of our observational study was
to assess the profile of endothelial function at the diagnosis
time as well as during initial phase of treatment and to verify
the presence of its correlation with an early clinical outcome.
2. Material and Methods
All experiments were conducted and approved in accordance
with the guidelines of the Bioethics Committee at Wroclaw
Medical University and adhered to the principles of the
Declaration of Helsinki and Title 45, US Code of Federal
Regulations, Part 46, Protection of Human Subjects (revised
November 13, 2001; effective December 13, 2001). All participants provided their informed consent which was followed by
its written approval by a legal representative, as appropriate.
The study and the written consent form had been approved
by the Bioethics Committee at Wroclaw Medical University.
BioMed Research International
Table 1: Baseline characteristics of ALL children and control group.
Study group
Control group
(mean ± SEM) (mean ± SEM)
N
28
18
Men (n)
12
6
Age (years)
8.1 ± 1
11 ± 0.9
ALT (U/L)
51.6 ± 32.3
17.7 ± 2.1
AST (U/L)
49.2 ± 13
22.8 ± 2.4
Urea (mg/dL)
25.4 ± 1.6
21.3 ± 1.6
Serum creatinine (mg/dL)
0.6 ± 0.0
0.6 ± 0.0
Plasma glucose (mg/dL)
100 ± 5.9
80.4 ± 1.1
Detailed baseline characteristics of the study group
(mean ± SEM)
CRP (mg/L)
23.2 ± 5.73
Total bilirubin (mg/dL)
0.57 ± 0.11
LDH ( kat/L)
10.4 ± 1.6
Total protein (g/dL)
6.8 ± 0.1
Uric acid (mg/dL)
5.9 ± 0.5
Sodium (mmol/L)
140 ± 0.4
Potassium (mmol/L)
4.2 ± 0.1
Parameter
p
ns
ns
ns
ns
0.02
ns
ns
0.02
Abbreviations. AST: aspartate transaminase. ALT: alanine transaminase.
hsCRP: C-reactive protein. LDH: lactate dehydrogenase. ns: not significant.
2.1. Patients and Controls. We have enrolled to our study 28
children with acute lymphoblastic leukemia and 18 healthy
demographically matched children (Table 1).
The study group included children with established
diagnosis of acute lymphoblastic leukemia treated strictly
according to the guidelines published in ALL-IC BMF 2002
protocol [13] (Figure 1(b)) in the Department of Pediatric
Bone Marrow Transplantation, Oncology and Hematology,
Wroclaw Medical University (Wroclaw, Poland). Children
were examined at the baseline (day of diagnosis), on the 33rd
and 78th day of therapy. At all three points, blood samples
had been obtained and endothelial function was assessed
(Figure 1(a)).
ALL children were categorized into three risk groups
(standard /n=8/, intermediate /n=14/, and high risk /n=6/).
Independently of this fact, during the first 78 days all of them
were treated in the same way with protocol I. The only difference was a doubled dose of daunorubicin in intermediate and
high risk groups. The protocol M was implemented for the
low-to-intermediate risk children, whereas the HR protocol
was used for children with high risk. This was followed in
turn by protocol II used in all the ALL children independently
on the baseline risk (Figure 1). Remission was observed in all
patients at the 33rd day of treatment.
The control group (n=18) was formed by healthy children
hospitalized at general pediatrics ward (Wroclaw Medical
University, Wroclaw, Poland) due to disorders that do not
affect endothelial function. Controls were examined only
once, since no changes in the profile of endothelial function
were suspected.
2.2. Biochemical Tests. Blood was collected using the Sarstedt S-Monovette system (Sarstedt AG & Co., Nümbrecht,
3
78th day
1st day
33rd day
BioMed Research International
SR
Protocol I
SR
Protocol M
IR
/64 days/
IR
/56 days/
HR protocols /3-6/
HR
Protocol II
Remission
maintenance
therapy
/49 days/
/74 weeks/
Protocol II
Remission
maintenance
therapy
/49 days/
/63 weeks/
HR
(a)
Pred.
p.o./i.v.
VCR
i.v.
DNR
p.i. (1h)
L-Asp
p.i. (1h)
CPM
p.i. (1h)
ARA-C i.v.
1
8
15
22
29
36
43
50
57
6-MP
p.o. (28 d)
MTX
i.t.
64
(b)
Figure 1: (a) Study design. (b) Treatment protocol. Protocol I in detail. Study covered the period of treatment common to all risk
groups. Abbreviations. Pred, prednisone 60 mg/m2 /d; VCR, vincristine 1.5 mg/m2 /d; DNR, daunorubicin 30 mg/m2 /d; L-Asp, L-Asparaginase
5000 U/m2 /d; CPM, cyclophosphamide 1000 mg/m2 /d; ARA-C, cytarabine 75 mg/m2 /d; 6-MP, 6-mercaptopurine 60 mg/m2 /dl; MTX,
methotrexate; p.o., per os; p.i., per infusion; i.t., intrathecal; d 1, day 1; d 33, day 33; SR, standard risk; IR, intermediate risk; HR, high risk.
Germany). Serum (7.5 mL) and EDTA plasma (9.0 mL;
1.6 mg-EDTA/ml of blood) were separated, immediately centrifuged (1000 x g for 15 minutes at 4∘ C), and frozen at −20∘ C
for evaluation markers of endothelial activation.
2.3. Markers of Endothelial Activation. Plasma concentrations of sP-selectin (CD62-P) and PAI-1 (serpin E1) and
serum concentrations of sE-selectin (CD62E), sICAM-1
(sCD54), sVCAM-1 (sCD106), and VEGF were determined
by a sandwich enzyme immunoassay technique, using commercial ELISA kits (R&D Systems Europe. Ltd., 19 Barton
Lane Abingdon Science Park OX14 3NB, United Kingdom)
according to the manufacturer’s instructions, kits catalogue numbers: BBE6, DSE100, DSLE00, DCD540, DVC00,
DVE00, respectively. The coefficient of variation (CV), intraassay %CV, was calculated as the ratio of the pooled standard
deviation from all samples (each was analyzed in triplicate)
and the overall mean and then multiplied by 100. Interassay %CV refers to assay-to-assay consistency that was
calculated using the pooled standard deviation divided by
the overall mean of all duplicated samples and then multiplied by 100. The intra-assay and inter-assay %CVs were,
respectively, 5.2% and 7.6% for sP-selectin, 6.1% and 7.2%
for PAI-1, 7.6% and 9.7% for sE-selectin, 5.3% and 7.1%
for sICAM-1, 3.7% and 7.6% for sVCAM-15.8, and 7.2% for
VEGF.
2.4. Other Biochemical Analyses. Concentrations of serum
creatinine, urea, fasting plasma glucose, Aspartate transaminase (AST), Alanine transaminase (ALT), lactate dehydrogenase (LDH), high sensitivity C-reactive protein (hsCRP),
potassium, and uric acid were measured using standard
commercial laboratory assays.
2.5. Statistical Analysis. Data is expressed as the mean ±
SEM. The differences between two continuous parameters
were assessed using a Mann-Whitney U-test or a Student’s
t-test, followed by a Shapiro-Wilk test and Levene’s test as
appropriate. For comparison of more than two groups, an
ANOVA followed by Tukey’s test or a Friedman ANOVA test
(for nonparametric statistics) was performed. Correlations
between continuous variables were calculated using Spearman test. All calculations were made using Statistica 10.0
StatSoft and the graphical representation of the data was
performed using GraphPad 5 Prism.
3. Results
3.1. General Characteristics of Groups. Both groups were similar regarding baseline demographic characteristics (Table 1).
According to the expectations, there were significant differences related to the complete peripheral blood cell counts
in children with ALL when compared to the control group
(Figure 2(a)). Fasting glycemia was higher in ALL children,
4
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