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Start of Phase Transition of Early Lung Cancer into Invasive Cancer Significantly Depended on Cell Ratio Factors Oleg Kshivets, MD, PhD

Kshivets O. Cancer, Synergetics and Immune Circuit

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Page 1: Kshivets O.   Cancer, Synergetics and Immune Circuit

Start of Phase Transition of Early Lung Cancer into Invasive Cancer Significantly Depended on Cell Ratio Factors

Oleg Kshivets, MD, PhD

Page 2: Kshivets O.   Cancer, Synergetics and Immune Circuit

Abstract:Start of phase transition of early lung cancer into invasive cancer significantly depended on cell ratio factors Kshivets Oleg Central City Hospital, Kachkanar, Russia

  Background: Significance of immune cell circuit for start of phase transition (PT) of early lung cancer into invasive cancer (LC) was investigated. Material and methods: In trial (1987-2012) consecutive cases after radical surgery (R0, bi/lobectomies=97, N2-lymphadenectomies=97; squamous=38, adenocarcinoma=54, large cell=5; G1=33, G2=40, G3=24), monitored 97 LC patients (LCP) (age=58.3±8.2 years, m=83, f=14); 48 early LCP (T1AN0M0, tumor size=1.7±0.3 cm, 5-year survival=100%), 49 invasive LCP (T1BN0M0, tumor size=2.9±0.1 cm, 5-year survival=77.6%). Variables selected for study were input levels of immunity blood parameters, sex, age, TNMG. The percentage, absolute count and total population number (per human organism) of CD3, CD19, CD4, CD8, CD16, CD1, CDw26, monocytes, CD4+2H, CD8+VV, leukocytes, lymphocytes, monocytes, eosinophils, stick and segmented neutrophils were estimated. Differences between groups were evaluated using discriminant analysis, clustering, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing. Results: It was revealed that start of PT early—invasive cancer significantly depended on cell ratio factors (ratio between blood cells subpopulations and cancer cells-CC): segmented neutrophils/CC, stick neutrophils/CC, CD3/CC, CD4+2H/CC, CDw26/CC (P=0.001-0.039). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships of PT early—invasive cancer and segmented neutrophils/CC (rank=1), CD16/CC (rank=2), CD4/CC (3), CD19/CC (4), CD4/CC (5), monocytes/CC (6), CD4+2H/CC (7). Correct detection of start of PT early—invasive cancer was 100% by neural networks computing (error=0.000; urea under ROC curve=1.0). Conclusions: Start of phase transition early—invasive lung cancer significantly depended on cell ratio factors.

Page 3: Kshivets O.   Cancer, Synergetics and Immune Circuit

Data:• Males………………………………………………….83• Females………..………………………………….......14• Age=58.3±8.2 years• Bi/Lobectomies with N2-Lymphadenectomies……..97• • Early Lung Cancer Patients (T1aN0M0; Tumor

Size=1.7±0.3 cm; 5-year Survival=100%)………….48• Invasive Lung Cancer Patients (T1bN0M0; Tumor

Size=2.9±0.1 cm; 5-year Survival=77.6%)…………49

Page 4: Kshivets O.   Cancer, Synergetics and Immune Circuit

Staging:• T1a.….48 N0..…..97 G1…………33• T1b…..49 N12……0 G2…………40• M1…….0 G3…………24• Adenocarcinoma………......................................54 • Squamos Cell Carcinoma………………………38 • Large Cell Carcinoma..………………………….5• Early Cancer (T1aN0M0)………………………48 • Invasive Cancer (T1bN0M0)…………………...49

Page 5: Kshivets O.   Cancer, Synergetics and Immune Circuit

Survival Rate:• Alive………………………………………....67 (69.1%)• 5-Year Survivors…………..………………..86 (88.7%) • Losses………………………………….…….11 (11.3%)• General Life Span=3983.5±1917.1 days• For 5-Year Survivors=4398.5±1613.5 days• For Losses=739.1±302.2 days

• Cumulative 5-Year Survival………………..88.7%• Cumulative 10-Year Survival………………82.7%

Page 6: Kshivets O.   Cancer, Synergetics and Immune Circuit

Immune Testing:

Page 7: Kshivets O.   Cancer, Synergetics and Immune Circuit

Factors of Immune Cell Circuit in Recognition of Phase

Transition Early—Invasive Lung Cancer (n=97)

Page 8: Kshivets O.   Cancer, Synergetics and Immune Circuit

General Lung Cancer Patients (T1abN0N0) Survival after Complete Bi/Lobectomies (Kaplan-Meier) (n=97)

Page 9: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Univariate Analysis of Phase Transition Early—Invasive Cancer in Prediction of Lung Cancer Patients Survival (n=97)

Page 10: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Discriminant Fanction Analysis in Recognition

of Phase Transition Early—Invasive Lung Cancer (n=97)

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Results of Multi-Factor Clustering of Immune and Blood Cell Factors in Recognition of Phase Transition Early—Invasive Lung Cancer (n=97)

Page 12: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Multi-Factor Clustering in Recognition of Phase Transition Early—Invasive Lung Cancer (n=97)

Logic Formulas Phase Transition Early—Invasive Cancer. Early Lung Cancer 0.73 <= Leucocytes/Cancer Cells (7.4%) <= 48.59 & 0.51 <= Segmented Neutrophils/Cancer Cells (6.7%) <= 34.02 & 0.20 <= Lymphocytes/Cancer Cells (7.4%) <= 13.49 & 0.06 <= T-Cells/Cancer Cells (6.7%) <= 9.41 & 0.08 <= CD4+Cells/Cancer ells (6.1%) <= 7.53 Objects=48 Error1=0.00 (0) Error2=0.00 (0) ────────────────────────────────────────────── Phase Transition Early—Invasive Cancer. Invasive Lung Cancer 0.15 <= Leucocytes/Cancer Cells ( 7.4%) <= 0.74 & 0.07 <= Segmented Neutrophils/Cancer Cells (6.7%) <= 0.53 & 0.03 <= Lymphocytes/Cancer Cells (7.4%) <= 0.25 & 0.01 <= T-Cells/Cancer Cells (6.7%) <= 0.14 & 0.01 <= CD4+Cells/Cancer Cells (6.1%) <= 0.13 Objects=49 Error1=0.00 (0) Error2=0.02 (1) ──────────────────────────────────────────────

Page 13: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Neural Networks Computing in Recognition of Phase Transition Early—Invasive Lung Cancer (n=97)

Error=0.000; Area under ROC Curve=1.00; Correct Classification Rate=100%

Factors: Rank Sensitivity

Segmented Neutrophils/Cancer Cells 1 32102.8

CD16+/Cancer Cells 2 15818.1

CD8+/Cancer Cells 3 1899.04

CD19+/Cancer Cells 4 921.551

CD4+/Cancer Cells 5 883.075

Monocytes/Cancer Cells 6 389.121

CD4+2H+/Cancer Cells 7 249.443

Page 14: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Bootstrap Simulation in Recognition of Phase

Transition Early—Invasive Lung Cancer (n=97)

Number of Samples=3333Significant Factors: Rank Kendall Tau-A P<

Lymphocytes/Cancer Cells 1 -0.505 0.000Segmented Neutrophils/Cancer Cells 2 -0.505 0.000Leucocytes/Cancer Cells 3 -0.505 0.000CD3+/Cancer Cells 4 -0.500 0.000CD4+/Cancer Cells 5 -0.500 0.000CD4+2H+/Cancer Cells 6 -0.497 0.000CD19+/Cancer Cells 7 -0.486 0.000CD16+/Cancer Cells 8 -0.471 0.000CD8+VV+/Cancer Cells 9 -0.467 0.000CD8+/Cancer Cells 10 -0.462 0.000Monocytes/Cancer Cells 11 -0.433 0.000CD1+/Cancer Cells 12 -0.421 0.000CDw26+/Cancer Cells 13 -0.385 0.000Eosinophils/Cancer Cells 14 -0.311 0.000Stick Neutrophils/Cancer Cells 15 -0.180 0.010CD8+VV+ tot 16 -0.164 0.017

Page 15: Kshivets O.   Cancer, Synergetics and Immune Circuit

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

0 5 1015202530

Killer-Cell Population

11.251.51.7522.252.52.75Cancer Cell Population

00

0.10.1

0.20.2

0.30.3

0.40.40.50.50.60.6

0.70.7

0.80.8

0.90.9

11

Phas

e Tra

nsiti

on

Phas

e Tra

nsiti

on

P=0.0000z=a+bx+cx 2̂+GCUMY(d,e,f)

r 2̂=1 DF Adj r 2̂=1 FitStdErr=8.4354944e-12 Fstat=6.8151355e+22a=1 b=5.7675827e-16 c=-1.8688846e-17

d=-1 e=2.2287067 f=-0.034448505

252015105B-Cell Population 1 1.251.51.752

2.252.52.75

Cancer Cells0 00.1 0.1

0.2 0.20.3 0.30.4 0.40.5 0.50.6 0.60.7 0.70.8 0.80.9 0.91 1

Phas

e Tra

nsiti

on

Phas

e Tra

nsiti

on

P=0.0000z=EXTRVALX(a,b,c)*EXTRVALY(1,d,e)

r 2̂=0.99790554 DF Adj r 2̂=0.99779046 FitStdErr=0.023494978 Fstat=10958.344a=1.2548733 b=2.4678053 c=7.9389194

d=2.7277315 e=0.3674437

Page 16: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Kohonen Self-Organizing Neural Networks Computing in Simulation in Recognition of Phase

Transition Early—Invasive Lung Cancer (n=97)

Page 17: Kshivets O.   Cancer, Synergetics and Immune Circuit

Lung Cancer Dynamics

Page 18: Kshivets O.   Cancer, Synergetics and Immune Circuit

Results of Structurul Equation Modeling in Recognition of Phase Transition

Early—Invasive Lung Cancer (n=97)

Page 19: Kshivets O.   Cancer, Synergetics and Immune Circuit

Conclusions:• Start of phase transition early—

invasive lung cancer significantly depended on cell ratio factors (ratio between blood cells subpopulations and cancer cells).

Page 20: Kshivets O.   Cancer, Synergetics and Immune Circuit

Address:Oleg Kshivets, M.D., Ph.D.Consultant Thoracic, Abdominal, General Surgeon & Surgical Oncologist

• e-mail: [email protected] • skype: okshivets • http: //www.ctsnet.org/home/okshivets