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Our experience of Embryonic Stem Cell Transplantation in the case of tumor disease treatments have permitted to identify its place at the stage of preparation for surgery, as well as following chemotherapy and radiotherapy.
Case reports
Tables
Application of embryonic cells for anti-cancer treatment
Center "EmCell" provides special aid to patients with secondary myelodepressive states, cytostatic disease, agranulocytosis, and primary pancytopenia in such medical institutions as Centers of Hematology, Research Institute of Oncology and Radiology, National Center of Proctology, Institute of Epidemiology and Infectious Diseases, Central Military Hospital.
The report on September 1998 contains analysis of treatment of 91 patients with various types of oncological diseases and at various stages: 42 patients with leukosis, 6 with carcinoma of the stomach, 8 with the carcinoma of the large intestine, 15 with cervical carcinoma, 4 with uterine carcinoma, 12 with osteogenic sarcoma, and 4 with Wilms' tumor. In 20 cases, embryonic cells were used at initial stages of treatment, in complications of tumors, before the carrying out main stages of treatment, and in 79 patients with cytostatic disease in remission, in order to restore the immunity and improve the quality of life in 16 patients.
We have described regularities of reactions and clinical pictures observed in patients that received cell therapy. The whole process of action is divided into two stages that differ in terms of the time of their development and clinical manifestations.
The first stage lasts about one month and involves early clinical symptoms occurring within several hours from transplantation. It is manifested by the syndrome of early posttransplantation improvement: improvement of general condition and appetite, decrease of temperature, weakness and sweating, restoration of self-service ability, and increase of working performance. This syndrome is most manifested in patients with symptoms of severe intoxication and can be most frequently observed in patients with severe progress of the disease.
The syndrome of psychofunctional changes is described: decrease of the somatic depression, improvement of emotional condition, thinking and memory, increase of the will component. We also single out syndrome of life quality improvement that always takes place in the use of Cell Therapy methods. Life quality has recently drawn special attention of the international medical community in connection with fatal diseases.
The initial stage of action includes the decrease in clinical manifestations associated with the progress of the disease; usually within first weeks improvement of hematopoiesis and immunity, decrease of main symptoms of the disease, decrease in the inflammatory activity etc could be observed.
The second stage of action, starts by 1 to 2 months from transplantation. It is associated with a decrease in the clinical manifestations of a disease: appearance of a stable hematopoiesis, improvement of immunity, decrease in inflammatory effects, increase in Karnofsky index, and improvement of the life quality.
Indications for embryonic cell transplantation in cancer patients:
in initial phase of treatment, if such complications as anemia, weakness, emaciation, thrombocytopenia, fever, depression do not permit to start radical treatment with tumor removal;
Application of this method prior to an operation permits to get a patient better prepared for the operation in cases of critical state and presence of complications; it also makes it easier for the patient to endure such operation and loss of blood, and to accelerate recuperation during the passage of the postoperative period. In addition, due to affecting the formation of antitumoral immunity, ESCT permits to reduce the probability of dissemination of the tumor cells and metastatic spreading. Patients subjected to preoperative ESCT have demonstrated as well better endurance of the initial course of chemotherapy. Cytostatic myelodepression after chemotherapy or radiotherapy, if there appears such complications as: leukopenia, agranulocytosis, thrombocytopenia, anemia, hepatitis, enteropathy, emaciation, depression, epillation, etc.; ESCT following the course of chemotherapy permits fast (5 to 7 days) restoration of normal peripheral blood indices, avoidance of numerous typical complications, and fast recovery of patient's general condition. The possibility of ESCT application allows, if required, extensive chemotherapy to be carried out with reduced risk for the patient's life. when the course of chemotherapy or radiotherapy is completed, in order to recover immune system, including NK-cells, as well as hematopoiesis, to improve general condition, remove weakness, reinforce psychoemotional condition, improve the quality of life.
Cell Therapy makes considerable contribution to antitumor immunity, which can be used in prophylactic of the tumor disease as well as in prophylactics of tumor relapses and metastazing.
In the fall of 1998 the cooperative scientific work of Embryonic Tissues Center "EmCell", Institute for Oncology and Radiology of Ministry of Health, and National Medical University on the elaboration and clinical trial of new methods with the use of Embryonic Stem Cell Transplantations for treatment of cancer patients, have been completed. The proposed new methods were approved by Ministry of Health on April 20, 1999, and recommended for clinical application.
Publications:
The peripheral blood counts in patients with oncological and hematological disturbances after Embryonic Stem Cells Transplantation (n=26)
| Term of observation |
Erythrocytes
1012/l
M±m |
Hemoglobin
g/l
M±m |
Thrombocytes
109/l
M±m |
Leukocytes
109/l
M±m |
| Before treatment |
2.65±0.15 |
78.19±4.25 |
79.40±16.42 |
1.37±0.16 |
| After ESCT (days) |
| 3 |
2.72±0.13 |
79.39±3.91 |
133.20±38.39 |
1.90±0.31 |
| 5 |
2.75±0.13 |
82.42±3.51 |
191.92±55.92 |
3.12±1.05 |
| 7 |
2.87±0.13 |
84.77±3.52 |
153.34±37.35 |
4.46±1.78 |
| 11 |
3.12±0.15 |
91.27±3.54* |
164.23±29.54* |
4.21±0.69*** |
| 13 |
3.40±0.16 |
96.19±3.50** |
212.65±37.95** |
4.68±0.89*** |
| 30 |
3.51±0.16 |
103.27±3.67*** |
163.73±20.00** |
5.20±1.01*** |
Contents of leukocytes in peripheral blood after chemotherapy in hematological patients after Embryonic Stem Cells Transplantation (n=26) and in a Control group (n=30)
| Days after Transplantation |
After Embryonic Stem Cells Transplantation (n=26) |
Control group (n=30) |
| |
M |
m |
% |
M |
m |
% |
| 0 |
1,37 |
0,16 |
100 |
1,20 |
0,07 |
100 |
| 3 |
1,90 |
0,31 |
138 |
1,17 |
0,09 |
97,5 |
| 5 |
3,12 |
1,05 |
228 |
- |
- |
- |
| 7 |
4,46 |
1,78 |
325 |
1,18 |
0,11 |
97,7 |
| 11 |
4,21* |
0,69 |
307 |
1,51 |
0,15 |
126 |
| 13 |
4,68* |
0,89 |
341 |
2,10 |
0,20 |
175 |
| 30 |
5,20* |
1,01 |
379 |
4,10 |
0,48 |
341 |
Recovery of total leukocytes and neutrophyls in hematological patients with severe postchemotherapy neutropenia after Embryonic Stem Cells Transplantation (n=16)
| Days after transplantation |
Total leukocytes |
Neutrophils |
| |
M |
m |
% |
M |
m |
% |
| 0 |
0.98 |
0.17 |
100 |
0.18 |
0.07 |
100 |
| 3 |
1.24 |
0.14 |
126 |
0.40 |
0.12 |
222 |
| 5 |
3.02 |
1.56 |
308 |
1.76 |
1.24 |
977 |
| 7 |
4.79 |
2.89 |
488 |
2.18 |
1627 |
|
| 11 |
3.59* |
0.91 |
366 |
1.79* |
0.76 |
994 |
| 13 |
3.78* |
1.17 |
385 |
2.06* |
0.95 |
1144 |
| 30 |
4.83* |
1.50 |
492 |
1.95* |
0.54 |
1083 |
Contents of leukocytes in peripheral blood after chemotherapy in hematological patients after Embryonic Stem Cells Transplantation (n=26) and in a Control group (n=30)
Days after transplantation
Recovery of total leukocytes and neutrophyls in hematological patients with severe postchemotherapy neutropenia after Embryonic Stem Cells Transplantation (n=16)
Days after transplantation
Peripheral blood indices in patients with cervical cancer after Cell Therapy (n=23)
| Blood indices |
St.in |
Before
Cell Therapy |
Days after Cell Therapy |
| 3 |
7 |
11 |
15 |
30 |
| Erythrocytes, *1012/l |
M
m
p |
3.60
0.11
|
3.54
0.19
|
3.59
0.16
|
3.62
0.17
|
4.05
0.21
|
3.89
0.19
|
| Hemoglobin, G/l |
M
m
p |
111.4
6.0
|
106.3
5.25
|
109.9
5.08
|
111.5
4.79
|
115.8
4.53
|
120.7
4.33
|
| Leukocytes, *109/l |
M
m
p |
2.66
0.29
|
3.14
0.53 |
3.83
0.49
<0.05 |
3.53
0.52
|
3.36
0.28
<0.05 |
3.55
0.24
<0.01 |
| Neutroph. steb, % |
M
m
p |
6.29
1.38
|
5.14
1.03
|
4.93
0.55
|
5.50
1.29
|
5.79
1.35
|
5.38
1.02
|
| Neutroph. steb, G/l |
M
m
p |
180.9
34.1
|
154.6
41.6
|
190.7
30.3
|
269.0
115.3
|
198.4
46.3
|
199.8
44.8
|
| Neutroph. segmented, % |
M
m
p |
54.3
2.56
|
58.6
2.73
|
58.7
2.38
|
64.1
2.57
<0.01 |
63.1
1.90
<0.005 |
64.7
2.54
<0.005 |
| Neutrophils segm., *109/l |
M
m
p |
1.48
0.20
|
1.84
0.31
|
2.29
0.33
<0.05 |
2.24
2.98
<0.05 |
2.04
0.16
<0.05 |
2.18
0.08
<0.05 |
| Lymphocytes, % |
M
m
p |
20.6
2.06
|
20.9
2.31
|
23.1
1.80
|
17.2
1.62
|
18.6
1.95
|
15.7
1.93
|
| Lymphocytes, *109/l |
M
m
p |
0.55
0.07
|
0.75
0.22
|
0.89
0.18
|
0.59
0.09
|
0.63
0.10
|
0.48
0.06
|
| Monocytes, % |
M
m
p |
8.21
0.86
|
9.29
1.15
|
9.64
1.04
|
8.50
1.47
|
7.14
1.03
|
8.23
1.27
|
| Monocytes, *109/l |
M
m
p |
0.21
0.02
|
0.27
0.04
|
0.34
0.04
0.05 |
0.32
0.08
|
0.23
0.03
|
0.27
0.05
|
Immune indices in patients with cervical cancer after Embryonic Stem Cells Transplantation
| Immunological tests |
Before
ESCT |
Two weeks
after ESCT |
After
radiotherapy |
| n=7 |
n=7 |
n=7 |
| M |
m |
M |
m |
M |
m |
| Leukocytes, *109/l |
2.90 |
0.14 |
3.91 |
0.38 |
3.54 |
0.40 |
| Lymphocytes, % |
16.00 |
4.62 |
16.71 |
2.13 |
20.14 |
3.84 |
| B-lymphocytes, (CD19+), % |
13.96 |
1.64 |
10.21 |
1.33 |
11.00 |
0.63 |
| B-lymphocytes, per mm3 |
66.34 |
23.74 |
68.02 |
15.5 |
70.76 |
8.75 |
| T-lymphocytes, (CD3+), % |
38.42 |
7.87 |
39.71 |
5.13 |
50.71 |
3.97 |
| T-lymphocytes, per mm3 |
168.98 |
67.03 |
254.90 |
58.9 |
332.62 |
54.16 |
| T-helpers (CD4+), % |
25.46 |
5.76 |
27.14 |
3.62 |
33.59 |
2.40 |
| T-helpers, mm3 |
112.11 |
47.36 |
177.90 |
44.9 |
220.12 |
34.76 |
| T-suppressers (CD8+), % |
12.31 |
2.66 |
15.08 |
1.56 |
18.86 |
2.01 |
| T-suppressers, mm3 |
59.85 |
26.95 |
95.65 |
17.9 |
121.17 |
18.50 |
| NK-cells (CD16+), % |
17.30 |
2.63 |
21.94 |
6.04 |
15.56 |
1.90 |
| NK-cells (CD16+), per mm3 |
84.55 |
32.98 |
129.87 |
34.3 |
95.01 |
8.79 |
| CD4+/CD8+ |
2.03 |
0.36 |
1.70 |
0.11 |
1.77 |
0.09 |
Effect of Embryonic Stem Cells Transplantation on experimental Lewis Carcinoma (LC) in mice.
| Conditions |
Tumor mass, g |
Number of metastases |
Volume of metastases, mm3 |
| LC, Control (n=10) |
4.2±0.4 |
4.5±0.3 |
3.7±0.5 |
| LC + Embryonic Stem Cell Transplantation (n=11) |
4.2±0.2 |
1.2±0.2 |
1.1±0.4 |
| In immunosupression |
| LC, Control |
6.9±0.3 |
12.5±1.6 |
14.6±4.4 |
| LC + Cyclophosphane |
5.6±0.3 |
60.4±3.1 |
123.4±24.6 |
| LC + Cyclophosphane + Embryonic Stem Cell Transplantation |
6.2±0.5 |
29.4±5.2 |
53.8±17.6 |
| In irradiation (4 Gr) |
| LC, Control |
1.0±0.5 |
1.1±0.3 |
6.5±3.1 |
| LC + Irradiation |
2.9±0.5 |
2.2±0.3 |
2.8±0.9 |
| LC + Irradiation + Embryonic Stem Cell Transplantation |
1.7±0.5 |
0.6±0.4 |
0.1±0.0 |
Psychophysiological changes in cancer patients after the Embryonic Stem Cell Transplantation
In the majority of cases, Embryonic Stem Cells Transplantation (ESCT) is followed by substantial changes in the volitional, mental and physical activities of patients, and is perceived as appearance of internal strength, confidence and hope, and disappearance of depressive tendencies.
75 clinical cases were analyzed: with cytostatic disease (50), without signs of cytostatic disease (25). Assessment of disorders of psychic condition, depressive symptoms, emotional changes, spirits, and changes of thinking, memory and intellect were carried out.
| |
Before
ESCT |
First 6-12 hours |
1-3
days |
5-10
days |
3-6
weeks |
3-6
months |
| State of spirit |
| depression |
+++ |
- |
- |
- |
- |
+ |
| composure, optimism |
- |
+ |
+ |
+ |
++ |
++ |
| desperation |
+++ |
- |
- |
- |
+ |
+ |
| tranquillity, hope |
- |
- |
+ |
+ |
++ |
++ |
| Emotional sphere |
| self awareness |
- |
+ |
++ |
+ |
++ |
++ |
| activity |
- |
++ |
+ |
++ |
++ |
++ |
| anxiety |
++ |
+ |
+ |
- |
- |
+ |
| stability of emotional state |
- |
+ |
+ |
++ |
++ |
++ |
| Mental capacity |
| Attention (strength and stability of concentration), |
+ |
++ |
+++ |
+ |
++ |
++ |
| Improvement of thinking process, memory, creativity, decreasing of manifestations of senile dementia |
+ |
+ |
++ |
++ |
+++ |
+++ |
| Improvement of contact with doctors and people around |
+ |
++ |
++ |
++ |
++ |
++ |
| Improvement of quality of sleeping |
- |
+ |
++ |
++ |
++ |
+ |
| Sexual energy |
- |
- |
+ |
++ |
+ |
+ |
Changes of patients' condition after Cell Therapy appear within a few hours starting with elevation of mood, volition, spirit, then of emotional and mental sphere, later on (in a few days) comes amelioration of internal body function and homeostasis, then, within few weeks, improvement of physical state develops. The effects lasts for several months. In very severe condition only some first effects of this row are observed.
The expression of manifestations depends on the severity of initial turnedcondition of patients. All the patients, from healthy to those with diseases of various severity and terminal stage patients are characterized in terms of effectiveness by reverse U-shaped curve. The place of oncological patients on this curve is from around the peek effect to the modest effect in terminal cases.
Positive psychophysiological changes occur in majority of patients with aggravated state (apathy, phobias, depression, general weakness, insomnia), during the hard trials caused
by diseases, and help them to overcome such trials through improvement of both physical and mental ability.
Amelioration of psychophysiological condition is a substantial contribution to the quality of life, especially in the incurable cases and stages of disease.
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