الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Acute Leukemias are hemopoietic neoplasms characterized by accumulation of blast cells in the bone marrow and peripheral blood.
AML also known as acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL), is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for approximately 1.2% of cancer deaths in the United States, its incidence is expected to increase as the population ages. AML is confirmed by an excess of primitive blast cells in the bone marrow required to be at least 20% and there is 8 subtypes of AML. Treatment and prognosis varies among subtypes. Five year survival varies from 15–70%, and relapse rate varies from 33–78%, depending on subtype. AML is treated initially with chemotherapy aimed at inducing a remission; patients may go on to receive additional chemotherapy or a hematopoietic stem cell transplant. Recent research into the genetics of AML has resulted in the availability of tests that can predict which drug or drugs may work best for a particular patient, as well as how long that patient is likely to survive.
ALL or acute lymphoid leukemia is an acute form of leukemia, or cancer of the white blood cells, characterized by the overproduction of cancerous, immature white blood cells—known as lymphoblasts. In persons with ALL, lymphoblasts are overproduced in the bone marrow and continuously multiply, causing damage and death by inhibiting the production of normal cells—such as red and white blood cells and platelets—in the bone marrow and by spreading (infiltrating) to other organs. ALL is most common in childhood with a peak incidence at 2–5 years of age, and another peak in old age. ALL may be B or T lineages and are classified by FAB classification into L1, L2, L3. The earlier ALL is detected, the more effective the treatment. The aim is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow).
Morphology remains the method by which acute Leukemia is initially detected and is the major aid with cytochemical reaction and immunophenotyping in distinguishing between ALL and AML.
The rennin-angiotensin system (RAS) is a bioenzymatic cascade that plays an integral role in cardiovascular homoeostasis by influencing vascular tone, fluid and electrolyte balance and the sympathetic nervous system.
The biological actions of the RAS are mediated primarily by the highly active octapeptide angiotensin II (Ang II). Traditionally, the RAS was viewed as a circulating endocrine system, whereby renin released from the juxtaglomerular cells of the kidney cleaves the liver-derived macroglobulin precursor angiotensinogen, to produce the inactive decapeptide angiotensin I, which is then converted to the active octapeptide Ang II by angiotensin converting enzyme (ACE) within the pulmonary.
There is increasing evidence that Ang II, a major regulator of blood pressure and cardiovascular homeostasis, is involved in the regulation of cell proliferation, angiogenesis, inflammation and tissue remodeling, which suggests that this peptide might also play a role in cancer.
Components of RAS are expressed in several adult organs including the liver, kidney, pancreas, brain and reproductive organs. It is the paracrine mechanisms of locally expressed RAS, not in its circulating counterpart, that appear important for tumorigenesis. Ang II is the main effector of the RAS and it alternatively binds to either Ang II T1R or Ang II T2R. The Ang II T1R and Ang II T2R can act as antagonists, and mediate effects on cell migration and proliferation of metastatic cancer cells and hemopoietic stem-progenitor cells. Components of the RAS are frequently differentially expressed in various cancers in comparison with their corresponding non- malignant tissue.
The Ang IIT1R belongs to the seven transmembrane class of G-protein-coupled receptors. Four cysteine residues are located in the extracellular domain, which represent sites of disulphide bridge formation and are critical tertiary structure determinants. The transmembrane domain and the extracellular loop play an important role in Ang II binding. The binding site for Ang II is different from the binding site for Ang IIT1R antagonists, which interacts only with the transmembrane domain of the receptor. Like most G-protein-coupled receptors, the Ang IIT1R is also subject to internalization when stimulated by Ang II.
Studies of knockout mice for ACE as well as other RAS components such as angiotensinogen, rennin, Ang II T1R and Ang II T2R have further implicated a regulatory role for the RAS in hematopoiesis. These mice have exhibited not only phenotypes related to blood pressure, but also demonstrated defects in development and in hematopoietic system. ACE null mice are mildly anemic, so it is presumed that the lack of systemic or local production of Ang II has a detrimental effect on erythropoiesis. Yet, the RAS has not been fully elucidated in patients with acute Leukemia.
For this reason, this study aimed to investigate serum level of Ang IIT1R and the soluble ACE (CD143) in patients with Acute Leukemia in order to extrapolate their possible prognostic value.
Individuals submitted to this study were divided into three groups:
Group I: Involved 20 healthy volunteers clinically free from hypertension or sarcoidosis (control group), their mean age was 33.25years and were chosen from the stuff members of MRI, Alexandria University, and clinical research center, Faculty of Medicine, Alexandria University and their relatives.
Group II: Involved 27 patients with newly diagnosed AML.
Group III: Involved 10 patients with newly diagnosed ALL.
Patients in group II and III were of matched age as the control group and were recruited from Hematology department, MRI, Alexandria University and clinical research center, Faculty of Medicine, Alexandria University. An informed consent was taken from all contributors in this study.
Patients with AML received 3 + 7 protocol of induction including: Daunomycin 45 mg/m2 for 3 days, Cytosine arabinoside 100 mg/ m2 x2 / day for 7 days. Patients with ALL received induction protocol as follows: Vincristine 1.4 mg/ m2 days 1, 8, 15, 22, Prednisolone 1 mg / kg / day x 28 days, Doxorubicin 25 mg/ m2 days 1, 2, 3. After completion of the cycles and restoration of bone marrow cellularity, bone marrow aspiration was done. Patients who achieved complete remission had a BM blasts less than 5%. Those who did not achieve complete remission received a 2nd induction cycle.
Statistical analysis was carried out using SPSS statistics software version 20. Quantitative data were tested for normality using Kolmogorov-Smirnov test. Abnormally distributed data was given as range and mean values ± SE.
The results showed that the activity of ACE (U/L) and the concentration of Ang IIT1R (U/L) in patients groups with either AML or ALL before therapy were significantly higher than in control group. After therapy, the activity of the enzyme and its receptor concentration in both groups of patients were significantly decreased but still significantly higher than in normal control subjects.
Moreover, the mean values of indirect bilirubin (mg/dl), total bilirubin (mg/dl) and SGPT (u/l) concentrations in both groups of patients were significantly higher than normal control group. In addition, the concentrations of direct bilirubin (mg/dl) as well as SGOT (u/l) in patients with ALL were significantly higher than normal control group. On the other hand, the mean values of albumin(mg/dl), creatinine (mg/dl), sodium (meq/l), potassium (meq/l), calcium (meq/l) and phosphorus (meq/l) concentrations in both groups of patients were significantly lower than in normal control group.
On the other hand, the mean value of WBCs count (x10e9) in both groups of patients were higher than in control group. On the other hand, Platelets count and Hb concentration in both groups of patients were significantly less than in normal subjects. Also, the blast cells % in patients with either AML or ALL before therapy was significantly higher than in control group. After therapy, the % of blast cells in both groups of patients were significantly decreased than their corresponding values before therapy and still significantly higher than in control group.
In AML patients group, ACE activity (U/L) showed a significant positive correlation with blast cells % at presentation. While in ALL patients groups, it was noticed that there was a significant positive correlation with blast cells % and Hb concentration (g/dl), and was inversely correlated with Phosphorus concentration (meq/l).
In addition, Ang IIT1R concentration (U/L) of AML patients group showed a significant positive correlation with blast cells % and urea concentration (mg/dl) at presentation. While in ALL patients groups, it was noticed that it was a significantly positive correlated with blast cells %, and was inversely correlated with WBCs count (x10e9) and Sodium concentration (meq/l).
The ROC curves analysis was used to compare the diagnostic values of serum ACE activity (U/L) and Ang IIT1R concentration (U/L) depending on the area under the curves (AUC). The higher AUC corresponds to a better diagnostic test. The curve showed that both parameters were excellent diagnostic markers of acute leukemia as was indicated by asymptomatic significance and very high area under the curve (100%, 100% respectively). The optimum cut off value of ACE activity (U/L) and Ang IIT1R concentration (U/L) were with a corresponding sensitivity 100% and specificity 100% for both parameters.
To study the prognostic values of these two parameters the Kaplan-Meier disease free survival (DFS) curves were constructed. For the first time, we could define a prognostic value for estimating the levels of ACE activity (U/L) and Ang IIT1R concentration (U/L) in patients with acute leukemia. The Kaplan-Meier disease free survival curve specified a cut off level for ACE < or > than 50.25 U/L with statistical significance (p < 0.00). This was true for Ang IIT1R as a cut off value of below or above 386 U/L could discriminate between a higher mean disease free survival of 24 months compared to 14 months in patients with higher level above the cut off point and the difference was statistically significant (p < 0.001) and this patients necessitating a more aggressive induction chemotherapy protocol
Conclusion
To the best of our knowledge the above study is the first to investigate the levels of serum ACE and its soluble receptor1 in patients with acute leukemia. We may conclude that estimating the serum level of ACE and soluble Ang IIT1R might be of informative diagnostic and prognostic value.
The findings of the present study make AR blockers and ACE inhibitors as a targeted option in the management of acute leukemia.
Recommendations
from the results of the present study we recommend the following:
1– Estimation of Ang II T1R and ACE levels in acute leukemia is of value in deciding the treatment protocol.
2– Further study on the other components of the RAS system is warranted.
3– Further studies on the impact of RAS on other hemopoietic neoplasms are to be envisaged namely the chronic leukemias and lymphomas.
4– Novel clinical applications of ACE inhibitors and Ang II T1R blockade in the management of acute leukemia is worthwhile.