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Early Detection and Phase Transitions in System “Malignancy-
Human Organism”
Oleg Kshivets, M.D., Ph.D.Siauliai Cancer Center, Lithuania
AACR Special Conference: The Biology and Genetics of Early Detection & Chemoprevention of Cancer
Miami, Florida, The USA, 1999
Abstract:• EARLY DETECTION AND PHASE TRANSITIONS IN SYSTEM “MALIGNANCY-HUMAN
ORGANISM” • Oleg Kshivets Siauliai Cancer Center, Siauliai, Lithuania
• Purpose: This research studied homeostasis parameters, typical for two extreme states of phase transition: early malignancy (strategic purpose of early detection) and invasive cancer (C).
• Methods: Basis of this research was the data of 1524 cancer patients (CP) with pathologic stage (T1-4N0-2M0-1G1-4): 655 gastric CP (GCP), 525 lung CP (LCP) and 344 bladder CP (BCP) operated and monitored in clinic 1970-1998. All CP had preoperation examination including peripheral blood count, biochemical tests of venous blood using usual unified methods, clinical, anthropometric, X-ray examination, endoscopy, sonography, electrocardiography and also doctor’s examination, if required, computed tomography and radioisotope scanning. After operations the data of intraoperational investigation, information on character of surgery, complications, morphologic C characteristics (size, TNMG, growth, histology, etc.) was registrated. Representativeness of samplings was reached by means of randomization based on unrepeated random selection. Multiple correspondence analysis (A), clustering, A of variance, confirmatory factor A, structural equation modeling and Monte Carlo simulation were used to determine any significant overall regularities between malignancy and CP organism.
• Results: Using complex system analysis, simulation modeling in terms of synergetics, evoinformatics, statements from theories of Hopf, Landau, Turing and Marchuk it was discovered that system “C-patient’s homeostasis” consecutively passed through three phase transitions: 1) phase transition “norm--oncobackground”; 2) phase transition “oncobackground--early malignancy”; 3) phase transition “early malignancy--invasive C”. If diagnosis of first two phase transitions depended on outcomes of early detection and diagnosis, identification of third phase transition resulted in effectiveness of treatment process and 5-year survival of CP. It was also verified that most important figure of this transition for human was quantity of C cell population in organism and average critical threshold of this population was 4.189e+9 per human organism. Below such value there was a temporal dynamic equilibrium between C and patient’s homeostasis and 5-year survival of radically operated CP tended to be 100%. Excess over this threshold resulted in irreversible consequences when effectiveness of treatment went down up to 10-15%. It was discovered that phase transition of early malignancy into invasive C of any localization significantly depended on: 1) input level of blood cell circuit; 2) ratio of C cell population quantity to blood cell subpopulations in integral CP organism (cell ratio factors); 3) C characteristics (C cell population quantity in CP organism, TNMG); 4) some blood biochemical factors; 5) anthropometric data.
•
Samplings:
• Lung Cancer Patients (T1-4N0-2M0-1)…….525• Gastric Cancer Patients (T1-4N0-2M0-1)….655• Bladder Cancer Patients (T1-4N0-2M0-1)…344• In All .………………………...……………..1524
• Patients with Non-Malignant Pathology….3977 • Practically Healthy Old People…………...1464
Prognostic Role of Cancer DiameterBivariate Histogram: Life Span and Bladder Cancer Diameter (cm)
Life Span (day)Bladder Cancer Diameter (cm)
No of obs
-20000 2000400060008000100001200014000
12345678910111213
20
40
60
80
100
Bivariate Histogram: Life Span of LCP and Cancer Diameter
n=404
Main Problem of Analysis of Living Supersystems:
Phenomenon of «Combinatorial Explosion»
• Average Number of Routine Blood Parameters:…… 28• Number of Possible Combination • for Random Search:……………….... n!=28!=3.049e+29 • Computer Operation Time of The 7G Teracomputer
(1000TFLOPS) (The 21st Century)… 9.7 Million Years
Basis
• NP RP P • n! n*n*2(e+n) or n log n n
• AI CSA+S+B SM
Model «Cancer Cells(Cr)--Human Killer Cells(Kl)»
• Ćr=Cr(1-Kl·μCr/λKl);• Ќl=(Kl·μCr/λKl)·[25·Cr/(4.189+• +2.5·Cr)-Cr-1];
Regularities between Dynamics Cancer Cell Population and Patient's Survival Rate
Phase Transitions in System «Homeostasis-Malignancy»
The Three Phase Transitions in the System «Malignancy-Human’s Organism»
Phase Transition Early Malignancy into Invasive Cancer
Role of Cell Ratio Factors in Phaze Transition Erly Cancer into Invasive Cancer
Regression Models (Lym/CC--Life Span of GCP, n=224; BCP, n=120 and LCP, n=162; 18th Degree Polynomial Fit): y=a+bx+cx2+dx 3+...
Lym/CC--Life Span LCP (n=162); r=0.263;P<0.01
X Axis (Lym/CC)
Y A
xis (
Life
Spa
n)
0.0 0.9 1.8 2.7 3.6 4.5 5.4
Lym/CC--Life Span BCP (n=120); r=0.296;P<0.01
X Axis (Lym/CC)
Y A
xis (
Life
Spa
n)
0.0 1.1 2.3 3.4 4.5 5.6 6.7
Lym/CC--Life Span GCP (n=224); r=0.328;P<0.001
X Axis (Lym/CC)
Y A
xis (
Life
Spa
n)
0.0 1.4 2.8 4.2 5.5 6.9 8.3
Cell Ratio Factors in Prognosis5-Year Survival Cancer Patients
Normal Probability PlotNormalized Residuals
Lung Cancer Patients (n=404) Model: Cell Ratio Factors-Survival
Value
Exp
ecte
d N
orm
al V
alue
-3
-2
-1
0
1
2
3
-4 -2 0 2 4 6 8 10 12 14
Normal Probability PlotNormalized Residuals
Gastric Cancer Patients (n=376) Model: Cell Ratio Factors-Survival
Value
Exp
ecte
d N
orm
al V
alue
-3
-2
-1
0
1
2
3
-3 -2 -1 0 1 2 3 4 5
Normal Probability Plot
Normalized Residuals
Bludder Cancer Patients (n=344)
Model: Cell Ratio Factors-Survival
Value
Exp
ecte
d N
orm
al V
alue
-3
-2
-1
0
1
2
3
-2 0 2 4 6 8
Results of Monte Carlo Simulation
-2,334 -1,897 -1,461 -1,024 -0,587 -0,150 0,286 0,723 1,160 1,597 above
From: Monte Carlo Data -- Replication 1 (bl1.sta)
Bludder Cancer Patients (n=344)
Cell Ratio Factors in Prediction of BCP Survival
-0,046 0,209 0,463 0,718 0,973 1,227 1,482 1,736 1,991 2,245 above
From: Monte Carlo Data -- Replication 1 (lc1.sta)Lung Cancer Patients (n=404)
Cell Ratio Factors in Prediction LCP Survival
-0,731 -0,593 -0,455 -0,317 -0,179 -0,041 0,097 0,235 0,372 0,510 above
From: Monte Carlo Data -- Replication 1 (gc11.sta)Gastric Cancer Patients (n=376)
Cell Ratio Factors in Prediction GCP Survival
Results of Structural Equotion Modeling
Normal Probability Plot (Conf.Modeling)Normalized Residuals
Lung Cancer Patients (n=404)
Model: Survival-Blood Cell Circuit-Cancer-Biochem.Homeostasis
Value
Exp
ecte
d N
orm
al V
alue
-3,5
-2,5
-1,5
-0,5
0,5
1,5
2,5
3,5
-16 -12 -8 -4 0 4 8 12 16
Bludder Cancer n=344Struct.Eq.Modeling
Normal Probability PlotNormalized Residuals
Bludder Cancer Patients (n=344)Model: Survival-Blood Cell Circuit-Cancer-Biochem.Homeostasis
Value
Exp
ecte
d N
orm
al V
alue
-3
-2
-1
0
1
2
3
-8 -4 0 4 8 12
Normal Probability PlotNormalized Residuals
Gastric Cancer Patients (n=376)
Model: Survival-Blood Cell Circuit-Cancer-Biochem.Homeostasis
Value
Exp
ecte
d N
orm
al V
alue
-3,5
-2,5
-1,5
-0,5
0,5
1,5
2,5
3,5
-16 -10 -4 2 8 14 20
Early and Differential Diagnosis of Malignancies
The Results of Multiple Correspondence and Claster Analysis of Blood Indexes in
Oncoscreening
Interdependencies between Blood Parameters, Indexes and Cancer Cell
Population
Interdependencies between Blood Indexes and Immune System of Cancer Patients
Networks Between Phase Transition “Early Cancer-Invasive Cancer”, Life Span and
Homeostasis Data
Superoncoscreeng-1.0SUPERONCOSCREENING-1.0
SCREENING ANTHROPOMETRY ANAMNESIS LOCALIZATION
SCR-1 SCR-2
SCR-3
ANT-1 ANT-2
ANT-3
LOC1 LOC12LOC2 LOC13LOC3 LOC14LOC4 LOC15LOC5 LOC16LOC6 LOC17LOC7 LOC18LOV8 LOC19LOC9 LOC20LOC10 LOC21 LOC11
MALIGNANT NEOPLASM STATISTICS
PRECANCER
NORM
LOC22
MALE FEMALE
Superoncodiagnos-1.0SUPERONCODIAGNOSIS-1.0
DIAGNOSIS-1 DIAGNOSIS-2 PRECANCER
NORM
MALIGNANT NEOPLASM LOCALIZATION
POPULATION PHASE TRANSITION STATISTICS
EARLY CANCER INVASIVE CANCER
Superoncodiagnosis of Metastasazing-1.0
SUPERONCODIAGNOSIS OF METASTASING-1.0
MTS-N MTS-M
MET-1 MET-2 DEP-1 DEP-2
LOCALIZATION MTS
LIVER LUNGCANCEROMATOSISBONES BRAINKIDNEY ADRENALSOVARY SKIN
STAGING STATISTICS MTS
POPULATION MC
PHASE TRANSITION
PT1 PT2 PT3
C1 C2GENERALIZATION
ST1 ST2 ST3EARLY MALIGNANCY
INVASIVE MALIGNANCY
MALIGNANCY OF THE II-III STAGES MALIGNANCY OF THE IV STAGE
Superoncoimmunology-1.0SUPERONCOIMMUNOLOGY-1.0
IMMUNODIAGNOSIS-1 IMMUNODIAGNOSIS-2
IMMUNODEFICIENCY NORMMALIGNANT NEOPLASM
POPULATION PHASE TRANSITION IMMUNOSTAGING
N M G
EARLY CANCER INVASIVE CANCER
Superoncoprognosis-1.0
SUPERONCOPROGNOSIS-1.0
PROGNOSIS SURVIVAL-2
PROG-1 PROG-2 PROG-3 E
SURVIVAL LESS 5 YEARS SURVIVAL MORE 5 YEARS
SURVIVAL-1
A B
C
Total Monitoring System
SOS-1.0HEALTHY PEOPLE
PRECANCER
PERSONS FOR SUSPICION OFMALIGNANCY
SOD-1.0
SOI-1.0NONMALIGNANT
PATHOLOGY
MALIGNANCY
SODM-1.0 EARLY CANCER
INVASIVE CANCER SOP-1.0
II-III STAGES IV STAGE
POPULATION OF THE COUNTRY
Conclusions:• 1. System “Cancer-patient’s homeostasis” consecutively passed
through three phase transitions: “norm-oncobackground”; “oncobackground-early malignancy”; “early malignancy-invasive cancer”.
• 2. Most important figure of this transition for human was quantity of cancer cell population in organism and average critical threshold of this population was 4.189e+9 per human organism.
• 3. Phase transition of early malignancy into invasive cancer of any localization significantly depended on: input level of blood cell circuit; ratio of cancer cell population quantity to blood cell subpopulations in integral cancer patient’s organism (cell ratio factors); malygnancy characteristics (cancer cell population quantity in organism, TNMG); some blood biochemical factors and anthropometric data.
Patents:1. Kshivets O.M. Method of Screening and Differential Diagnosis of Malignant
Neoplasms// Patent from 27.04.92.-N2045072.-28pp.. 2. Kshivets O.M. Method of Prognosis of Survival Rate of Radically Operated
Oncopatients// Patent from 10.02.94.-N2101704.-24pp. .3. Kshivets O.M. Method of Prognosis of Survival Rate of Non-Radically Operated
Oncopatients// Patent from 14.03.94.-N2104536.-10pp. .4. Kshivets O.M. Method of Early and Differential Immunodiagnosis of Malignancies//
Patent from 24.10.95.-N2107290.-12pp. .5. Kshivets O.M. Method of Immunodiagnosis of Distant Metastases of Oncopatients//
Patent from 06.10.95.-N2107295.-8pp. .6. Kshivets O.M. Method of Immunodiagnosis of Generalization of Oncopatients// Patent
from 09.10.95.-N2107294.-12pp. .7. Kshivets O.M. Method of Immunodiagnosis of Early and Invasive Oncopathology for
Patients// Patent from 04.05.95.-N2107293.-14pp. .8. Kshivets O.M. Method of Differential Diagnosis of Oncopathology and Pre-Cancer or
Non-Malignant Pathology// Patent from 08.11.94.-N2114431.-18pp.
Patents:. 9.Kshivets O.M. Method of Measuring the Size of Malignant Neoplasms and Total Quantity of
Malignant Cells in Oncopatient’s Organism Based on the Homeostasis Parameters// Application for Patent from 04.05.95.-N95107201/012623.-8pp. (Positive Decision).
.10. Kshivets O.M. Method of Diagnosis of Distant Metastases of Oncopatients// Application for Patent from 03.11.95.-N95118236/032006.-12pp. (Positive Decision).
.11. Kshivets O.M. Method of Diagnosis of Generalization of Oncopatients// Application for Patent from 20.10.95.-N95117904/031312.-12pp. (Positive Decision).
.12. Kshivets O.M. Method of Diagnosis of Early and Invasive Oncopathology for a Single Patient// Application for Patent from 06.10.95.-N95117338/029690.-13pp. (Positive Decision).
.13. Kshivets O.M. Method of Diagnosis of Malignant Neoplasms Metastasizing in Regional Lymphatic Nodules of a Concrete Patient// Application for Patent from 29.09.95.-N95116510/028981.-10pp. (Positive Decision).
.14. Kshivets O.M. Method of Measuring the Size of the Malignancy and Total Quantity of Malignant Cells in the Oncopatient’s Organism Based on the Immunogram// Application for Patent from 04.05.95.-N95107200/012622.-9pp. (Positive Decision).
.15. Kshivets O.M. Method of Immunodiagnosis of Regional Metastases of Oncopatients// Application for Patent from 06.10.95.-N95117049/029707.-9pp. (Positive Decision).
Address:• Oleg Kshivets, M.D.,
Ph.D.• Thoracic Surgeon• Department of Surgery• Siauliai Cancer Center• Tilzes:42-16, Siauliai, LT78206, Lithuania• Tel. (37041)416614• [email protected] • [email protected]• http//:myprofile.cos.com/Kshivets