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• okshivets@yahoo.com • kshivets@gmail.com• http//:myprofile.cos.com/Kshivets