Kshivets O. Lung Cancer Surgery

LYMPH NODE METASTASES OF LUNG LYMPH NODE METASTASES OF LUNG CANCER AND IMMUNE SYSTEMCANCER AND IMMUNE SYSTEM

Oleg Kshivets, MD, PhDOleg Kshivets, MD, PhD Siauliai Cancer Center, Siauliai, LithuaniaSiauliai Cancer Center, Siauliai, LithuaniaThe Second International Chicago Symposium on

Malignancies of The Chest and Head & NeckChicago, Illinois, The USA, 2001

Abstract:Abstract: LYMPH NODE METASTASES OF LUNG CANCER AND IMMUNE SYSTEMLYMPH NODE METASTASES OF LUNG CANCER AND IMMUNE SYSTEM Oleg Kshivets Siauliai Cancer Center, Siauliai, Lithuania Oleg Kshivets Siauliai Cancer Center, Siauliai, Lithuania Purpose: Significance of immune cell and humoral circuit in terms of detection of lung cancer (LC) patients (LCP) with lymph node metastases was investigated. Methods: In trial (1987-1998) consecutive cases after surgery, monitored 533 LCP (males – 472, females – 61; age=57.40.4 years; pneumonectomies -181, upper lobectomies - 138, lower lobectomies - 67, upper/lower bilobectomies - 24, middle lobectomies – 6, segmentectomies – 76, exploratory thoracotomies and biopsies - 41) with pathologic stage I-IV (stage I – 48, stage II – 47, stage III - 321; stage IV – 117; squamous cell LC - 294, adenocarcinoma - 171, large cell LC – 48, small cell LC - 20; T1 - 116, T2 - 168, T3 – 125, T4 - 124; N0 – 148, N1 - 144, N2 - 159; N3 – 82; G1 – 88, G2 – 166, G3 – 279; M0 – 438; M1 - 95) were reviewed. Variables selected for study were input levels of immunity blood parameters, sex, age, TNMG. Thawed aliquoted samples were evaluated for IgG, IgM, IgA, natural antibodies, circulating immune complexes. The percentage, absolute count and total population number (per human organism) of T-lymphocytes (CD3), B-lymphocytes (CD19), helper T-lymphocytes (CD4), suppressor/cytotoxic T-lymphocytes (CD8), killer cells (O-cells, K-cells or CD16), precursor T-cells (CD1), activated T-cells (CDw26), monocytes (CD64, CD13), helper/inducer T-lymphocytes (CD4+2H), contrsuppressor T-lymphocytes (CD8+VV), CD4/CD8, leukocytes, lymphocytes, polymorphonuclear and sticknuclear leukocytes were estimated. The laboratory blood studies also included input levels of NST (tests of oxygen dependent metabolism of neutrophils spontaneous and stimulated by Staphylococcus aureus or by Streptococcus pyogenes), index of stimulation of leukocytes by Staphylococcus aureus or Streptococcus pyogenes, index of thymus function, phagocytic number, phagocyte index, index of complete phagocytosis. Differences between groups were evaluated using multiple regression analysis, multi-factor clustering, structural equation modelling and Monte Carlo simulation. Results: It was revealed that separation of LCP with lymph node metastases (males – 343, females – 42; age=57.2±0.4 years; T1-4N1-3M0-1; tumor size=6.1±0.1 cm; n=385) from LCP without metastases (males – 129, females – 19; age=57.9±0.6 years; T1-3N0M0, tumor size=3.5±0.2 cm; n=148) significantly (P=0.000000) depended on: 1) level of immune cell circuit (2=31263.7; Df=560); 2) value of monocyte and macrophage circuit (2=233.9; Df=14); 3) level of humoral immunity (2=183.66; Df=9); 4) neutrophils circuit (2=7261.35; Df=77); 5) value of cell ratio factors (ratio of LC cell population to immune cell subpopulations in integral LCP organism) (2=6907.08; Df=104); 6) LC characteristics (T1-4, M0-1,G1-3, histology, tumor size) (2=1103.58; Df=27). It was also founded that most important factors of metastases of LC in lymph nodes were cell ratio factors (T=-5.761; P=0.0000000) and LC characteristics (T=9.666; P=0.0000000).

Key words: Lung Cancer, Immunity, Lymph Node Metastases

The Main Characteristics of The Main Characteristics of The Study PopulationsThe Study Populations

Lung Cancer Patients (males – 472, females – 61; age=57.40.4 years)…..533

Stage I…………..……………………...48Stage II…………………..……………..47Stage III……………………………….321Stage IV……………………………….117

Procedures (n=533)Procedures (n=533)Pneumonectomy………………………181Upper Lobectomy…………………….138Lower Lobectomy.……………………..67Upper/Lower Bilobectomy…….………24Middle Lobectomy………………………6Segmentectomy.……………………..…76Exploratory Thoracotomy, Biopsy…...41 Combined & Extensive Procedures with Resection of

Pericardium, Left Atrium, Aorta, Vena Cava Superior, Vena Azygos, Carina, Trachea, Diaphragm, Chest Wall, Ribs, etc. ………………….…………….55

Lung Cancer Patients Lung Cancer Patients Characteristics (n=533)Characteristics (n=533)

Squamous Cell……..294 Adenocarcinoma…...171 Large Cell……………48 Small Cell…………….20 T1.…………………..116 T2……………………168 T3……………………125 T4……………………124 N0……………………148

N1…………………...144 N2…………………...159 N3………………….…82 G1…………………….88 G2…………………...166 G3…………………...279 M0…………………...438 M1…………………….95

Immune Testing:Immune Testing:

Significant Immune Data in Detection of Lung Cancer Lymph Node Significant Immune Data in Detection of Lung Cancer Lymph Node Metastases (n=533)Metastases (n=533)

NN Factors N0 n=148 N1-3 n=385 P Mean SD Mean SD 1 2

B-cells (abs)*109/l B-cells (tot)*109

0.36 1.76

0.37 1.84

0.31 1.48

0.18 0.92

0.027* 0.020*

3 CD4+2H (abs)*109/l CD4+2H (tot) *109

0.59 2.83

0.41 1.89

0.51 2.46

0.34 1.78

0.018* 0.037*

CD8 (%) CD8 (tot) *109

14.03 1.17

8.20 0.89

12.50 1.01

7.79 0.78

0.045* 0.045*

6 Lymphocytes (%) 30.57 10.78 27.07 11.10 0.001* 7 8

NST spontaneous NST stimulated Streptococcus Pyogenes

7.33 9.55

6.30 8.63

9.16 11.73

9.15 9.71

0.026*

0.017* 9 Index Stimulation by Streptococcus

pyogenes 1.46

0.013*

10 11 12 13

Leukocytes (abs)*109/l Segmented Neutrophils (%) Segmented Neutrophils (abs)*109/l Segmented Neutrophils (tot)*109

5.94 61.78 3.69 17.84

2.32 11.14 1.60 8.20

6.45 65.17 4.25 20.12

2.53 11.49 1.96 9.30

0.031* 0.002* 0.002* 0.009*

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

T-cells/Cancer Cells B-cells/Cancer Cells K-cells/Cancer Cells CD1/Cancer Cells CDw26/Cancer Cells CD4+2H/Cancer Cells CD8+VV/Cancer Cells CD4/Cancer Cells CD8/Cancer Cells Leukocytes/Cancer Cells Eosinophils/Cancer Cells Lymphocytes/Cancer Cells Monocytes/Cancer Cells Stick Neutrophils/Cancer Cells Segmented Neutrophils/Cancer Cells

1.76 0.73 1.02 0.31 0.19 1.11 1.13 1.40 0.47 10.99 0.31 3.43 0.40 0.12 6.72

1.60 1.24 1.79 0.52 0.33 1.08 1.36 1.29 0.58 8.72 0.37 3.94 0.50 0.20 5.25

0.78 0.28 0.47 0.14 0.09 0.47 0.47 0.64 0.19 5.62 0.31 1.52 0.18 0.08 3.65

0.62 0.22 0.43 0.21 0.14 0.41 0.49 0.57 0.17 3.09 0.27 1.09 0.21 0.14 2.09

0.000000* 0.000000* 0.000000* 0.000000* 0.000002* 0.000000* 0.000000* 0.000000* 0.000000* 0.000000* 0.000053* 0.000000* 0.000000* 0.004333* 0.000000*

Results of Logistic Regression Modeling in Detection of Lymph Node Results of Logistic Regression Modeling in Detection of Lymph Node

Metastases of Lung Cancer (n=533)Metastases of Lung Cancer (n=533) NN Significant Immune Factors: 2=47.281; Df=14;

P=0.00002; n=533; Estimate

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Const.B0 CD4+2H (abs)*109/l CD4+2H (tot)*109 CD8 (%) CD8 (tot) *109 B-cells (abs)*109/l B-cells (tot)*109 NST spontaneous NST stimulated Streptococcus pyogenes Index Stimulation by Streptococcus pyogenes Leukocytes (abs)*109/l Lymphocytes (%) Segmented Neutrophils (%) Segmented Neutrophils (abs)*109/l Segmented Neutrophils (tot)*109

-2.60217 -4.62834

0.82 -0.01852 -0.04143 1.64540 -0.62571 0.06071 -0.02167 0.26358

0.48 0.01332 0.03823 -0.02550 -0.09027

ExpectedNormal

Frequency Distribution (Residuals): Lung Cancer Patients with Stage I-IVLogistic Regression (N0-N1-3---Immune System)

Chi2=47.28; Df=14; P=0.00002; n=533

-1,2 -1,0 -0,8 -0,6 -0,4 -0,2 0,0 0,2 0,4 0,6 0,8 1,0

Correlation between Lymph Node Metastasis & Lung Cancer Characteristics (n=533)Correlation between Lymph Node Metastasis & Lung Cancer Characteristics (n=533)

13,545 26,991 40,436 53,882 67,327 80,773 94,218 107,664 121,109 134,555 above

Bivariate Histogram: Lung Cancer Cell Population & Lymph Node MetastasesLung Cancer Patients with Stage I-IV, n=533

r=0.50; P=0.0000

-0,083 0,034 0,151 0,268 0,384 0,501 0,618 0,735 0,852 0,969 above

Quadratic SurfaceLung Cancer Cell Population vs. G1-3 vs. NO---N1-3

r (Lung Cancer Cell Population vs. NO---N1-3)=0.50; P=0.000 r (Lung Cancer Cell Population vs. G1-3)=0.27; P=0.000

r(G1-3 vs. NO---N1-3)=0.31; P=0.000

T- & B-cell Circuit in Detection of Lung T- & B-cell Circuit in Detection of Lung Cancer Lymph Node Metastases (n=533)Cancer Lymph Node Metastases (n=533)

CD8- & CD4-cell Circuit in Detection of Lung CD8- & CD4-cell Circuit in Detection of Lung Cancer Lymph Node Metastases (n=533)Cancer Lymph Node Metastases (n=533)

Lymphocytes & Monocytes Circuit in Detection Lymphocytes & Monocytes Circuit in Detection of Lung Cancer Lymph Node Metastasesof Lung Cancer Lymph Node Metastases (n=533) (n=533)

K-cells Circuit & Cancer Cells Number in K-cells Circuit & Cancer Cells Number in Detection of Lung Cancer Lymph Node Detection of Lung Cancer Lymph Node

Metastases (n=533)Metastases (n=533)

Segmented Neutrophils & CD4+2H-cells Circuit Segmented Neutrophils & CD4+2H-cells Circuit in Detection of Lung Cancer Lymph Node in Detection of Lung Cancer Lymph Node

Cancer Cells Number & G1-3 in Detection of Cancer Cells Number & G1-3 in Detection of Lung Cancer Lymph Node Metastases (n=533)Lung Cancer Lymph Node Metastases (n=533)

Humoral Immunity in Detection of Lung Humoral Immunity in Detection of Lung Cancer Lymph Node Metastases (n=533)Cancer Lymph Node Metastases (n=533)

Cancer Cells Number & Cancer Cells Number & Lymphocytes Lymphocytes in in Detection of Lung Cancer Lymph Node Detection of Lung Cancer Lymph Node

Role of Cell Ratio Factors in Lymph Node Metastases of Role of Cell Ratio Factors in Lymph Node Metastases of Lung Cancer (n=533)Lung Cancer (n=533)

Pareto Chart of t-Values for Coefficients; df=502Variable: NO---N1-N3 (Multiple R=0.529; P=0.00000)Sigma-restricted parameterization: Cell Ratio Factors

Lung Cancer Patients with Stage I-IV (T1-4N0-3M0-1), n=533

t-Value (for Coefficient;Absolute Value)

.0017443.3030983.3379894.3759631

.5061909.56716.5855403.6148093

.7795556

.7844907.7909309.8093222.8143432.8234021

.93423771.0256651.0449641.059058

1.1895431.225681.251766

1.4075021.457586

1.6227741.738972

1.9701382.216493

2.8545283.320651

3.893053

Eosinophils/CC^2Leucocytes/CC^2

CD8+VV/CCB-cells/CC^2

Segm.Neutrophils/CC^Monocytes/CC^2

Stick Neutrophils/CCMonocytes/CC

CDw26/CCSegm.Neutrophils/CC

T-cells/CC^2Leucocytes/CC

Stick Neutrophils/CCCD8+VV/CC^2Eosinophils/CC

K-cells/CCLymphocytes/CC

Lymphocytes/CC^2CDw26/CC^2

T-cells/CCB-cells/CC

CD4+2H/CC^2K-cells/CC^2

CD1/CC^2CD8/CC^2

CD1/CCCD4+2H/CC

CD4/CC^2CD4/CCCD8/CC

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5

Results of Multi-Factor Clastering of Immune Results of Multi-Factor Clastering of Immune Factors in Detection of Lung Cancer Lymph Factors in Detection of Lung Cancer Lymph

Node Metastases (n=533)Node Metastases (n=533)

Networks between Factors of Immune Cell and Networks between Factors of Immune Cell and Humoral Circuit and LC Characteristics (n=533)Humoral Circuit and LC Characteristics (n=533)

SEPATH Modeling of System Lumph Node SEPATH Modeling of System Lumph Node Metastases--Immune System of Lung Metastases--Immune System of Lung

Cancer Patients (n=533)Cancer Patients (n=533)

N0--N1-3--T-, B-, K-Cell Circuit-Humoral Immunity-Macrophage Circuit--Neutrophil Circuit-Cell Ratio Factors-Lung Cancer

Global Model: Normalized Residuals (Lymph Node Metastases)Chi2=73226.4; Df=3154; P=0.000000; n=533

-25 -15 -5 5 15 25 35

Results of Monte Carlo Simulation (n=533)Results of Monte Carlo Simulation (n=533)

-1,849 -1,277 -0,706 -0,134 0,437 1,009 1,580 2,152 2,723 3,295 above

Monte Carlo Simulation: Lung Cancer Patients with Stage I-IV, n=533Model: N0---N1-3--T-, B-, K-cell Circuit--Humoral Immunity--Monocyte/Macrophage

--Neutrophils Circuit--Cell Ratio Factors--Cancer CharacteristicsP=0.000000

-3,675 -3,349 -3,024 -2,699 -2,374 -2,048 -1,723 -1,398 -1,073 -0,747 -0,422 -0,097 0,229 0,554 0,879 1,204 1,530 above

Monte Carlo Data Simulation: Lung Cancer Patients with Stage I-IV, n=533Model: N0---N1-3--T-, B-, K-cell Circuit--Humoral Immunity--Monocyte/Macrophage

Neutrophils Circuit-Cell Ratio Factors--Cancer CharacteristicsP=0.000000

-0,972 -0,475 0,022 0,520 1,017 1,514 2,011 2,508 3,006 3,503 above

--Neutrophils Circuit--Cell Ratio Factors--Cancer CharacteristicsP=0.000000

-2,376 -1,739 -1,101 -0,464 0,174 0,812 1,449 2,087 2,725 3,362 above

Neutrophils Circuit--Cell Ratio Factors--Cancer CharacteristicsP=0.000000

Immune Networks in Detection of Lymph Node Immune Networks in Detection of Lymph Node Metastasis in Lung Cancer Patients (n=533)Metastasis in Lung Cancer Patients (n=533)

0 2 4 6 8 10 122

6Model "Early Cancer---Immune System"

Lung Cancer Cell Population

10.0590.235 X1 2 X2 2

X3 2 X4 2

0 5 10 15 200

200 X1 1

0 5 10 15 20 25 3010

10Model "Invasive Cancer---Immune System"

10.187

25.4662.403 10 14 X1 2 X2 2

X3 2 X4 2

0 5 100

8.691 10 14

100 X4 1

Lotka-Volterra Models of Lung Cancer Cell Population Lotka-Volterra Models of Lung Cancer Cell Population and Cytotoxic Cell Population Dynamicsand Cytotoxic Cell Population Dynamics

Holling-Tenner Models of Lung Cancer Cell Population Holling-Tenner Models of Lung Cancer Cell Population and Cytotoxic Cell Population Dynamics and Cytotoxic Cell Population Dynamics

0 5 100

100.103 X1 2 X2 2

X3 2 X4 2

0 50 100 150 200 2500

2000 X1 1

0 5 10 15 200

13.007

19.5124 X1 2 X2 2

X3 2 X4 2

0 20 40 600

500 X4 1

Neural Networks in Detection of Lymph Node Metastases by Immune Factors & Neural Networks in Detection of Lymph Node Metastases by Immune Factors & Tumor Characteristics of Lung Cancer Patients (n=533)Tumor Characteristics of Lung Cancer Patients (n=533)

N0 N1-3 N0 N1-3 N0 N1-3Total 73 194 32 101 43 90Correct 55 159 30 77 34 73Wrong 18 35 2 24 9 17Unknown 0 0 0 0 0 0N0 55 35 30 24 34 17N1-3 18 159 2 77 9 73

T. Back PropagationV. Back PropagationT. Con.Gradient DescV. Con.Gradient DescT. Quasi-newtonV. Quasi-newton

Training Error Graph (Sum-squared)Lung Cancer Patients with Stage I-IV (T1-4N0-3M0-1), n=533

Neural Network (Linear): Immune System---Lymph Node Metastases

0 100 200 300 400 500

Receiver Operating Characteristic (ROC) curveLung Cancer Patients with Stage I-IV (T1-4N0-3M0-1), n=533

1-Specificity

0.0 0.5 1.0

T. Levenberg-MarquarV. Levenberg-MarquarT. Quick PropagationV. Quick PropagationT. Delta Bar DeltaV. Delta Bar Delta

0 100 200 300 400 500

Neural Networks in Detection of Lymph Node Metastases by Immune Neural Networks in Detection of Lymph Node Metastases by Immune Factors of Lung Cancer Patients (n=533)Factors of Lung Cancer Patients (n=533)

N0 N1-3 N0 N1-3 N0 N1-3 Total 69 198 28 105 51 82 Correct 59 159 21 78 34 59 Wrong 10 39 7 27 17 23 Unknown 0 0 0 0 0 0 N0 59 39 21 27 34 23 N1-3 10 159 7 78 17 59

Training Error Graph (Sum-squared)

Lung Cancer Patients with Stage I-IV (t1-4N0-3M0-1), n=533

0 100 200 300 400 500 600

T. Back PropagationV. Back PropagationT. Levenberg-MarquarV. Levenberg-MarquarT. Quick PropagationV. Quick PropagationT. Delta Bar DeltaV. Delta Bar Delta

Receiver Operating Characteristic (ROC) curveLung Cancer Patients with Stage I-IV (T1-4N0-3M0-1), n=533

1-Specificity

0.0 0.5 1.0 N0N1-3

Cluster Diagram (NO---N1-3)Lung Cancer Patients with Stage I-IV (T1-4N0-3M0-1), n=533

Neural Network (Linear), Layer 1: Immune System---Lymph Node Metastases

T-cell Population

0 4 8 12 16

Training & Verification of Neural Networks in Recognition of Lymph Node Training & Verification of Neural Networks in Recognition of Lymph Node Metastases by Immune Factors of Lung Cancer Patients (n=533)Metastases by Immune Factors of Lung Cancer Patients (n=533)

N0 N1-3 N0 N1-3 N0 N1-3 Total 86 247 26 74 36 64 Correct 84 245 15 57 18 55 Wrong 2 2 11 17 18 9 Unknown 0 0 0 0 0 0 N0 84 2 15 17 18 9 N1-3 2 245 11 57 18 55 ---------------------------------------------------------------------------------------------------------------------------------------------- Genetic N0-N1-3 CD4+2H PhN S% Lym% E/CC S/CC M/CC Algorithm Yes Yes Yes Yes Yes Yes Yes Selection Useful T/CC CD4+2H/CC CD1/CC CD8/CC Yes Yes Yes Yes ----------------------------------------------------------------------------------------------------------------------------------------------

Neural Network (PNN): Immune System---N0-N1-3

0 50 100 150 200 250 300

Training by Levenberg-MarquardtVerification by Levenberg-Marquardt

Lung Cancer DynamicsLung Cancer Dynamics

Conclusions:Conclusions: It was revealed that separation of lung cancer

patients with lymph node metastases from patients without metastases significantly depended on:

1) level of immune cell circuit; 2) value of monocyte and macrophage circuit; 3) level of humoral immunity; 4) neutrophils circuit; 5) value of cell ratio factors; 6) lung cancer characteristics.

Address:Address:

Oleg Kshivets, M.D., Ph.D. Thoracic Surgeon Department of Surgery Siauliai Cancer Center Tilzes:42-16, 5400 Siauliai, Lithuania Tel. (37041)416614 okshivets@yahoo.com kshivets@hotmail.com http//:myprofile.cos.com/Kshivets

Kshivets O. Lung Cancer Surgery

Health & Medicine

Kshivets O. Lung Cancer Surgery

Kshivets O. Esophageal Cancer Surgery

Kshivets O. Lung Cancer Surgery

Lung volume reduction surgery ( LVRS )

Lung surgery of Yekaterinburg

Lung surgery

Kshivets O. Synergetics and Survival of Lung Cancer Patients

A Guide to Lung Surgery - MUHC Patient Educationv~lung-surgery-montreal... · A Guide to Lung Surgery This booklet is to help you understand and prepare for your surgery. Please review

Kshivets O. Esophagogastric Cancer Surgery

Kshivets O. Lung Cancer: Role of Adjuvant Chemoimmunoradiotherapy after Surgery

Kshivets O. Lung Cancer Stage III Surgery

Lung volume reduction surgery

Lung Surgery 1

Kshivets O. Lung Cancer Surgery: Synergetics and Prediction

My lung surgery - Roy Castle Lung Cancer Foundation · 2 My lung surgery My lung surgery 3 Introduction If you or someone you care for has lung cancer and surgery is a possible treatment,

Kshivets O. Esophageal and Cardioesophageal Cancer Surgery

Kshivets sso2013

Advance in Lung Cancer Surgery

Kshivets O. Lung Cancer: Immune System and Prognosis

Kshivets milan2014