Download - Kshivets O. Lung Cancer Surgery: Prognosis

HOMEOSTASIS NETWORKS IN PROGNOSIS OF LUNG CANCER PATIENTS SURVIVAL

Oleg Kshivets, M.D., Ph.D.Department of Surgery, Siauliai Cancer Center, Lithuania

The 9th World Conference on Lung CancerTokyo, Japan, 2000

Abstract Homeostasis networks in prognosis of lung cancer patients survival O.Kshivets. Siauliai Cancer Center, Siauliai, Lithuania Purpose: The influence of homeostasis networks on 5-year survival (5YS) and life span (LS) of lung cancer (C) patients

(LCP) after radical procedures was investigated. Methods: In a randomized trial (1970-1999) cases of radically operated and monitored consecutive 404 LCP (male=363,

female=41; pneumonectomy=175, upper lobectomy=136, lower lobectomy=66, middle lobectomy=6, bilobectomy=21) with pathologic stage II-III (T1-N0-2M0; squamos cell C=263, adenocarcinoma=116, large cell C=25; stage II=111, stage III=293; T1=118, T2=187, T3=84, T4=15; N0=223, N1=97, N2=84; G1=100, G2=104, G3=200) were reviewed. 242 LCP (age=55.9±0.5 years; LS=2417.7±42.7 days; tumor diameter: D=4.1±0.1 cm) lived more than 5 years without any features of C progressing. 162 LCP (age=56.5±0.6 years; LS=576.0±30.6 days; D=4.7±0.2 cm) died because of relapses and generalization of C during the first 5 years after radical procedures. Variables selected for 5YS study were input levels of 46 blood and biochemic parameters, coagulogram, sex, age, TNMG, cell type, D. Representativeness of all samplings was reached by means of randomization based on unrepeated random selection. Multiple correspondence analysis (A), multi-factor clustering, A of variance, confirmatory factor A, structural equation modeling and Monte Carlo simulation were used to determine any significant overall regularities between 5YS (LS) and LCP homeostasis.

Results: It was revealed that 5YS and LS of radically operated LCP (n=404) significantly depended on: 1) phase transition of early LC into invasive LC; 2) input level of blood cell subpopulations circuit; 3) ratio of C cell population quantity to blood cell subpopulations quantity in integral LCP organism (cell ratio factors: CRF); 4) LC characteristics (C cell population quantity, TNMG-system); 5) biochemic homeostasis; 6) hemostasis system; 7) anthropometric data. Structural equation modeling and Monte Carlo simulation confirmed significant overall networks between 5YS (LS) of LCP and blood cell subpopulations circuit (2=10485.5; k=169; T=4.747; P=0.000002), biochemic homeostasis (2=239.6; k=64; T=-3.64; P=0.0003), phase transition of early C into invasive C (2=5.540; k=1; T=3.711; P=0.0002), CRF (2=4017.8; k=43; T=4.377; P=0.00001), C characteristics (2=98.6; k=13; T=-4.635; P=0.000003); hemostasis system (2=211.6; k=34; T=6.814; P=0.000000); anthropometric data (2=157.3; k=8; T=3.50; P=0.0004).

Samplings:

Lung Cancer Patients Lived More than 5 Years after Complete Resections..…...242

Lung Cancer Patients Died Because Generalization During First 5 Years after Complete Resections.…….…………...162

In All…………………………………...404

Samplings: Adjuvant

Chemoimmunoradiotherapy…………..54 Postoperative Radiotherapy..……...…..86 Surgery Alone…………………………264 In All…………………………………...404

Radical Procedures: Pneumonectomy…………………..175 Upper/Lower Bilobectomy…………21 Upper Lobectomy…………………136 Lower Lobectomy………………….66 Middle Lobectomy………………….6 Combined Procedures……………..49 In All…………………………...….404

Main Problem of Analysis of Living Supersystems (e.g. Lung Cancer Patient Homeostasis):

Phenomenon of «Combinatorial Explosion»

Average Number of Routine Blood Parameters:….. 46 Number of Possible Combination for Random Search:

……………..………………….. n!=46!=5.5e+57 Operation Time of The 7G Superteracomputer

(1000TFLOPS) (The 21st Century)…….1.7e+35 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];

Prognostic Role of Lung Cancer Diameter

Bivariate Histogram: Life Span of LCP and Cancer Diameter

n=404

Clinicopathologic Nucloids of Lung Cancer Patients with N0-2, n=404

Results of Cluster-Analysis of Clinicopathologic

Characteristics of Lung Cancer Patients with N0-2, n=404

Homeostasis Nucloids of Lung Cancer Patients with N0-2, n=404

Results of Cluster-Analysis of Homeostasis Data of Lung Cancer Patients with N0-2, n=404

Results of Correspondence Analysis of Pathologic Characteristics of Lung Cancer Patients with N0-2, n=404

Network-Model of Lung Cancer Patients with N0-2 (n=404)

Homeostasis Network-Model of Lung Cancer Patients with N0-2 (n=404)

Morphologic and Homeostasis Network-Model of Lung Cancer Patients with N0-2 (n=404)

Survival of Lung Cancer Patients with N0-2 (n=404)

Cumulative Proportion Surviving (Kaplan-Meier)Complete Censored

Lung Cancer Patients, n=404 (N0-N1-N2)Global Chi2=14.34; Df=2; P=0.00077

Time (months) after complete resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180 200

Only Complete Resections, n=264Postoperative Radiotherapy, n=86Adjuvant Chemoimmunoradiotherapy, n=54

Proportional Hazard (Cox) Regression Model of Lung Cancer Patients with N0-2, n=404

Survival Function for Mean Values of Independent VariablesProportional Hazard (Cox) Regression

Lung Cancer Patients, n=404 (N0-N1-N2)Chi2=129.33; Df=13; P=0.000000

Survival Time (Months)

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.55

0.60

0.65

0.70

0.75

0.80

0.85

0.90

0.95

1.00

1.05

0 20 40 60 80 100 120 140 160 180 200

Logistic Regression Model of Lung Cancer Patients with N0-2, n=404

ExpectedNormal

Frequency Distribution: ResidualsLung Cancer Patients with N0-2, n=404

Logistic Regression ModelsChi2=109.27; Df=13; P=0.0000000

No

of o

bs

0102030405060708090

100110120

-1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2



Lung Cancer Patients, n=404 (N0-N1-N2)Global Chi2=92.32; Df=2; P=0.000000000

Time (munths) after complete resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180 200

N0, n=223N1, n=97N2, n=84



Lung Cancer Patients, n=181 (N1-N2)Global Chi2=11.951; Df=2; P=0.00254

Time (monts) after complete resections

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160

Only comlete Resections, n=89Posoperative Radiotherapy, n=59Adjuvant Chemoimmunoradiotherapy, n=33

Cluster-Analysis of Data of Early and Invasive Lung Cancer Patients

Phase Transition Early Malignancy into Invasive Cancer

Results of Monte Carlo Simulation: Phase Transition—Survival of LCP

-1.263 -1.005 -0.746 -0.488 -0.230 0.028 0.287 0.545 0.803 1.062 above

From: Monte Carlo Data -- Replication 1 (lc1.sta)Lung Cancer Patients, n=404

Chi2=1217.569; df=2; P<0.0000000 Model: Phase Transition Early Cancer-Invasive Cancer---Survival

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»

Regression Models (Cell Ratio Factors--Life Span of LCP, n=162; 18th Degree Polynomial Fit): y=a+bx+cx2+dx 3+...

Lymphocytes/CC--Life Span of LCP; n=162; r=0.259;P=0.000

Lymphocytes/Cancer Cells

Life

Spa

n (D

ays)

0.0 0.9 1.8 2.7 3.6 4.5 5.4

Monocytes/CC--Life Span of LCP; n=162; r=0.350;p=0.000

Monocytes/Cancer Cells

Life

Spa

n (D

ays)

0.0 0.2 0.5 0.7 0.9 1.2 1.4

Segmented Neutrophils/CC--Life Span of LCP; n=162;r=0.271; P=0.000

Segmented Neutrophils/Cancer Cells

Life

Spa

n (D

ays)

0.1 3.3 6.5 9.7 12.9 16.1 19.4

Leukocytes/CC--Life Span of LCP; n=162; r=0.266;P=0.000

Leukocytes/Cancer Cells

Life

Spa

n (D

ays)

0.2 4.1 8.1 12.0 16.0 19.9 23.9


Erhytrocytes/CC--Life Span of LCP; n=162; r=0.391;P=0.000

Erhytrocytes/Cancer Cells

Life

Spa

n (D

ays)

0.0 2.0 4.0 6.0 8.0 10.0 12.0

Thrombocytes/CC--Life Span of LCP; n=162; r=0.435;P=0.0000

Thrombocytes/Cancer Cells

Life

Spa

n (D

ays)

7.3 110.3 213.4 316.4 419.4 522.5 625.5

Healthy Cells/CC--Life Span of LCP; n=162; r=0.321;P=0.000

Healthy Cells/Cancer Cells

Life

Spa

n (D

ays)

0.8 7.2 13.5 19.8 26.2 32.5 38.8


Eosinophils/CC--Life Span of LCP; n=162; r=0.278;P=0.000

Eosinophils/Cancer Cells

Life

Spa

n (D

ays)

0.0 0.1 0.3 0.4 0.5 0.6 0.8

Stick Neutrophils/CC--Life Span of LCP; n=162; r=0.283;P=0.000

Stick Neutrophils/Cancer Cells

Life

Spa

n (D

ays)

0.0 0.1 0.3 0.4 0.5 0.7 0.8

Cell Ratio Factors in Prognosis of 5-Year Survival Lung 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

Results of Monte Carlo Simulation:Cell Ratio Factors—Survival of LCP

-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

Results of Structural Equation 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

Networks Between Lung Cancer Patients Survival and System “Cancer- Homeostasis”

Superoncoprognosis-1.0SUPERONCOPROGNOSIS-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

Conclusions: 5-year survival and life span of lung cancer patients (n=404)

after complete resections significantly depended on: 1) phase transition of early cancer into invasive cancer; 2) input level of blood cell subpopulations circuit; 3) cell ratio factors: ratio of cancer cell population number to

blood cell subpopulations number in integral lung cancer patient organism;

4) cancer characteristics (cancer cell population number, TNMG-system);

5) the data of blood biochemical homeostasis; 6) hemostasis system; 7) 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 Patients with

Malignant Neoplasms. Patent from 10.02.94; N2101704: 24pp. 3. Kshivets O.M. Method of Prognosis of Survival Rate of Non-Radically Operated Patients with

Malignant Neoplasms. Patent from 14.03.94; N2104536: 10pp. 4. Kshivets O.M. Method of Early and Differential Immunodiagnosis of Malignant Neoplasms.

Patent from 24.10.95; N2107290: 12pp. 5. Kshivets O.M. Method of Immunodiagnosis of Distant Metastases for Patients with Malignant

Neoplasms. Patent from 06.10.95; N2107295: 8pp. 6. Kshivets O.M. Method of Immunodiagnosis of Generalization for Patients with Malignant

Neoplasms. Patent from 09.10.95; N2107294: 12pp. 7. Kshivets O.M. Method of Immunodiagnosis of Early and Invasive Malignancy for Patients.

Patent from 04.05.95: N2107293: 14pp. 8. Kshivets O.M. Method of Differential Diagnosis of Malignancy and Pre-Cancer or Non-

Malignant Pathology. Patent from 08.11.94; N2114431: 18pp. 9. Kshivets O.M. Method of Measuring the Size of Malignant Neoplasms and Total Number of

Malignant Cells in Oncopatient’s Organism Based on the Homeostasis Parameters. Patent from 04.05.95; N2135996: 8pp.

Patents:10. Kshivets O.M. Method of Diagnosis of Distant Metastases for Patients with

Malignant Neoplasms. Patent from 03.11.95; N2134878: 12pp. 11. Kshivets O.M. Method of Diagnosis of Generalization for Patients with Malignant

Neoplasms. Patent from 20.10.95; N2132059: 12pp. 12. Kshivets O.M. Method of Diagnosis of Early and Invasive Malignancy for a Single

Patient. Patent from 06.10.95; N2133466: 13pp. 13. Kshivets O.M. Method of Diagnosis of Malignant Neoplasms Metastasizing in

Regional Lymphatic Nodules for a Concrete Patient. Patent from 29.09.95; N2131606: 10pp.

14. Kshivets O.M. Method of Measuring the Size of the Malignancy and Total Number of Malignant Cells in the Oncopatient’s Organism Based on the Immunogram. Patent from 04.05.95; N2135995: 9pp.

15. Kshivets O.M. Method of Immunodiagnosis of Regional Metastases for Patients with Malignant Neoplasms. Patent from 06.10.95; N2131607: 9pp.

Address:

Oleg Kshivets, M.D., Ph.D. Thoracic Surgeon Department of Surgery Siauliai Cancer Center Tilzes:42-16, Siauliai, LT78206, Lithuania Tel. (37041)416614 Fax (37041)526430 [email protected] [email protected] http//:myprofile.cos.com/Kshivets

Download - Kshivets O. Lung Cancer Surgery: Prognosis

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