1.
ARTFICIAL INTELLIGENCE, SYSTEM ANALYSIS AND SIMULATION MODELING IN PREDICTION OF 5-YEAR SURVIVAL OF CARDIOESOPHAGEAL CANCER PATIENTS AFTER COMPLETE LEFT THORACOABDOMINAL ESOPHAGOGASTRECTOMIES Oleg Kshivets, MD, PhD Department of Surgery, Siauliai Public Hospital & Cancer Center, Lithuania The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

2.
Abstract <ul><li>ARTFICIAL INTELLIGENCE, SYSTEM ANALYSIS AND SIMULATION MODELING IN PREDICTION OF 5-YEAR SURVIVAL OF CARDIOESOPHAGEAL CANCER PATIENTS AFTER COMPLETE LEFT THORACOABDOMINAL ESOPHAGOGASTRECTOMIES </li></ul><ul><li>Oleg Kshivets Department of Surgery, Siauliai Public Hospital & Cancer Center, Siauliai, Lithuania </li></ul><ul><li>OBJECTIVE: We examined the clinicomorphologic factors associated with the low- and high-risk of generalization of cardioesophageal cancer (CEC) (T1-4N0-3M0) after complete esophagogastrectomies (EG) through left thoracoabdominal incision. METHODS: We analyzed data of 150 consecutive CEC patients (CECP) (age=54.9±0.7 years; tumor size=6.9±0.2 cm) radically operated and monitored in 1975-2006 (males=116, females=34; combined EG with resection of pancreas, liver, diaphragm, colon transversum, splenectomies=49; lymphadenectomy D2=59, D3=91; esophagogastroanastomosis=89, esophagoenteroanastomosis=61; adenocarcinoma=125, squamos=19, mix=6; T1=16, T2=32, T3=58, T4=44; N0=59, N1=18, N2=71; N3=2; G1=42, G2=30, G3=78). Variables selected for 5-year survival (5YS) study were input levels of 45 blood parameters, sex, age, TNMPG, cell type, tumor size. Survival curves were estimated by the Kaplan-Meier method. Differences in curves between groups of CECP were evaluated using a log-rank test. Multivariate Cox modeling, multi-factor clustering, discriminant analysis, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing were used to determine any significant dependence. RESULTS: 44 CECP (life span: LS=3545.8±238.7 days) lived more than 5 years without any features of CEC progressing (5YS=29.3%). 106 CECP died because of generalization of CEC during the first 5 years after radical procedures (LS=593.5±32.6 days). Cox modeling displayed that 5YS of CECP (n=150) after complete EG significantly depended on: T1-4, combined procedures, histology, G1-3, blood lymphocytes, monocytes, neutrophils, lymphoid infiltration of CEC, age (P=0.000-0.038). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS of CECP and combined procedures (rank=1), N0-3 (2), histology (3), gender (4), CEC growth (5), type of operations (6), P1-4 (7), T1-4 (8), adjuvant chemoimmunotherapy (9), G1-3 (10), blood coagulation time (11), blood lymphocytes (12), thrombocytes (13), blood rest nitrogen (14), hemorrhage time (15), ESS (16), age (17), weight (18), blood chlorides (19), tumor size (20). CONCLUSIONS: Correct prediction of CECP survival after radical procedures was 90.7% by logistic regression (odds ratio=86.7), 96% by discriminant analysis and 100% by neural networks computing (area under ROC curve=1.0; error=0.0012). </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

3.
Data <ul><li>Males…………………………………………….. 116 </li></ul><ul><li>Females………..………………………………….. 34 </li></ul><ul><li>Age=54.9±0.7 years </li></ul><ul><li>Tumor Size=6.9±0.2 cm </li></ul><ul><li>Only Surgery.…………………………………... 132 </li></ul><ul><li>Adjuvant Chemoimmunotherapy (5FU+thymalin/taktivin, 5-6 cycles)……………. 18 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

4.
Radical Procedures <ul><li>Proximal Esophagogastrectomies with Single-Stage Esophagogastroplasty.…………………. 81 </li></ul><ul><li>Total Esophagogastrectomies with Single-Stage Esophagoenteroplasty..………..……………… 69 </li></ul><ul><li>Combined Esophagogastrectomies with Resection of Diaphragm, Liver, Mesocolon, Colon Transversum, Splenectomy, Left Hemipancreatectomy, etc……………………. 49 </li></ul><ul><li>Lymphadenectomy D2………………………... 59 </li></ul><ul><li>Lymphadenectomy D3………………………... 91 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

5.
Schemas of Procedures The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

6.
Procedures

7.
One-Stage Esophagogastroplasty or Esophagoenteroplasty

8.
Schemas of Combined Procedures The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

9.
Schemas of D3 Lymphadenectomy The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

10.
Staging <ul><li>T1…… 16 N0..….. 59 G1………… 42 </li></ul><ul><li>T2…… 32 N1…… 18 G2………… 30 </li></ul><ul><li>T3…… 58 N2…… 71 G3………… 78 </li></ul><ul><li>T4…… 44 N3…….. 2 </li></ul><ul><li>exophytic growth………….. 53 </li></ul><ul><li>endophytic growth……….... 85 </li></ul><ul><li>mix growth..……………….. 12 </li></ul><ul><li>adenocarcinoma…………… 93 </li></ul><ul><li>squamos cell carcinoma…… 52 </li></ul><ul><li>mix carcinoma………………. 5 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

11.
Survival Rate <ul><li>5-Year Survivors…………..……. 44 (29.3%) </li></ul><ul><li>10-Year Survivors………………. 18 (12.0%) </li></ul><ul><li>Losses…………………………… 106 (70.7%) </li></ul><ul><li>General Life Span= 1459.5 ±132 days </li></ul><ul><li>For 5-Year Survivors= 3545.8±238.7 days </li></ul><ul><li>For Losses= 593.5±32.6 days </li></ul><ul><li>Cumulative 5-Year Survival……. 29.3% </li></ul><ul><li>Cumulative 10-Year Survival…... 22.4% </li></ul><ul><li>Cumulative 15-Year Survival…... 20.2% </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

12.
General Cardioesophageal Cancer Patients Survival after Complete Left Thoracoabdominal Esophagogastrectomies (Kaplan-Meier) ( n=150 ) The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

13.
Results of Univariate Analysis in Prediction of Cardioesophageal Cancer Patients Survival ( n=150 )

14.
Results of Univariate Analysis in Prediction of Cardioesophageal Cancer Patients Survival ( n=150 )

15.
Results of Univariate Analysis in Prediction of Cardioesophageal Cancer Patients Survival ( n=150 ) The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

16.
Results of Cox Regression Modeling in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Factors Wald df P Exp(B) 95%CI for Exp(B) Lower Upper </li></ul><ul><li>Eosinophils% 6.539 1 0.011 1.802 1.147 2.829 </li></ul><ul><li>Stick.Neutrophils% 12.447 1 0.000 2.298 1.447 3.648 </li></ul><ul><li>Seg.Neutrophils% 14.680 1 0.000 2.379 1.527 3.706 </li></ul><ul><li>Lymphocytes% 11.949 1 0.001 2.212 1.410 3.469 </li></ul><ul><li>Monocytes% 12.832 1 0.000 2.303 1.459 3.634 </li></ul><ul><li>T1-4 12.579 3 0.006 </li></ul><ul><li>T(1) 11.124 1 0.001 0.196 0.075 0.510 </li></ul><ul><li>T(2) 6.870 1 0.009 0.349 0.159 0.767 </li></ul><ul><li>T(3) 1.409 1 0.235 0.672 0.348 1.296 </li></ul><ul><li>Ad.CHIT 0.648 1 0.421 0.744 0.362 1.529 </li></ul><ul><li>Age 10.419 1 0.001 1.042 1.016 1.068 </li></ul><ul><li>Comb.operation 15.523 6 0.017 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

17.
Results of Cox Regression Modeling in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Factors Wald df P Exp(B) 95%CI for Exp(B) Lower Upper </li></ul><ul><li>Histology 15.864 2 0.000 </li></ul><ul><li>Histology(1) 13.556 1 0.000 8.361 2.700 25.894 </li></ul><ul><li>Histology(2) 15.753 1 0.000 9.631 3.147 29.473 </li></ul><ul><li>Lymphocytes abs 5.423 1 0.020 6.126 1.332 28.166 </li></ul><ul><li>Seg.Neutrophils abs 4.899 1 0.027 0.495 0.265 0.923 </li></ul><ul><li>G1-3 6.539 2 0.038 </li></ul><ul><li>G(1) 5.907 1 0.015 0.519 0.305 0.881 </li></ul><ul><li>G(2) 3.578 1 0.059 0.565 0.313 1.021 </li></ul><ul><li>LIT 32.081 3 0.000 </li></ul><ul><li>LIT(1) 25.546 1 0.000 6.648 3.189 13.858 </li></ul><ul><li>LIT(2) 23.429 1 0.000 5.804 2.848 11.829 </li></ul><ul><li>LIT(3) 1.084 1 0.298 1.424 0.732 2.768 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

18.
Results of Discriminant Analysis in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Discriminant Function Analysis Summary </li></ul><ul><li>Wilks' Lambda: 0.305 approx. F (61,88)=3.281 p< 0.0000 </li></ul><ul><li> Wilks' Partial F-remove P-level </li></ul><ul><li> Lambda Lambda (1,88) </li></ul><ul><li>LIT 0 .403 0.757 28.238 0.000 </li></ul><ul><li>Comb.Operation 0.319 0.956 4.032 0.048 </li></ul><ul><li>Erythrocytes 0 .319 0.956 4.012 0.048 </li></ul><ul><li>Weight 0 .319 0.958 3.893 0.052 </li></ul><ul><li>Glucose 0.318 0.962 3.503 0.065 </li></ul><ul><li>Growth 0.312 0.979 1.904 0.171 </li></ul><ul><li>G1-3 0.308 0.990 0.854 0.358 </li></ul><ul><li>Ad.CHIT 0.307 0.995 0.402 0.528 </li></ul><ul><li>T1-4 0.306 0.999 0.128 0.722 </li></ul><ul><li>N0-3 0.306 0.999 0.064 0.801 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

19.
Results of Logistic Regression Analysis in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li> Est. S.E. Wald P Odds 95.0% C.I.for Odds Ratio Ratio Lower Upper </li></ul><ul><li>Const.B 18.24 9.25 3.89 0.049 8.3e+7 0.95 5.8e+12 </li></ul><ul><li>Seg.Neut.% -0.21 0.10 4.44 0035 0.81 0.67 0.99 </li></ul><ul><li>Monocytes abs-5.46 2.51 4.74 0.030 0.00 0.00 0.608 </li></ul><ul><li>LIT 1.99 0.42 22.38 0.000 7.28 3.18 16.70 </li></ul><ul><li>G1-3 -0.59 0.42 2.02 0.155 0.55 0.24 1.26 </li></ul><ul><li>Growth 1.54 0.71 4.75 0.029 4.69 1.15 19.04 </li></ul><ul><li>Comb.Oper. -0.47 0.16 8.75 0.003 0.63 0.46 0.86 </li></ul><ul><li>T1-4 -0.26 0.48 0.29 0.589 0.77 0.30 1.99 </li></ul><ul><li>N0-3 -0.20 0.40 0.26 0.613 0.817 0.370 1.80 </li></ul>Chi2=105.11; df=15; P=0.0000 ; Odds ratio=86.70 The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

20.
Results of Correspondence Analysis in Prediction of Cardioesophageal Cancer Patients Survival (n=150) The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

21.
Results of Multi-Factor Clustering of Clinicopathological Data in Prediction of Cardioesophageal Cancer Patients Survival (n=150) The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

22.
Neural Networks in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li> Baseline Errors=0.0012 </li></ul><ul><li>Area under ROC curve=1 .00 </li></ul><ul><li>Correct Classification Rate= 100% </li></ul><ul><li> Losses 5-year survivors </li></ul><ul><li>Total 106 44 Correct 106 44 Wrong 0 0 </li></ul><ul><li>Genetic Algorithm Selection </li></ul><ul><li>Useful for L ESS Haemor.Time Protein PI D Histology G1-3 Growth Sabs </li></ul><ul><li>Survival Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes </li></ul><ul><li>Useful for Lymabs Comb.Oper. P1-4 L/CC S/CC T1-4 N0-3 Chlorides Stot </li></ul><ul><li>Survival Yes Yes Yes Yes Yes Yes Yes Yes Yes </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

23.
Results of Kohonen Self-Organizing Neural Networks Computing in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150) The 60th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

24.
Results of Neural Networks Computing in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) Error=0.0011; Area under ROC Curve=1.00; Correct Classification Rate=100% <ul><ul><li>Factor Rank Error Ratio </li></ul></ul><ul><li>Comb.Operat. 1 0.199 159.5 </li></ul><ul><li>N0-3 2 0.185 148.0 </li></ul><ul><li>Histology 3 0.172 138.0 </li></ul><ul><li>Sex 4 0.166 133.1 </li></ul><ul><li>Growth 5 0.164 130.9 </li></ul><ul><li>Oper. Type 6 0.153 122.6 </li></ul><ul><li>P1-4 7 0.117 94.0 </li></ul><ul><li>T1-4 8 0.109 87.2 </li></ul><ul><li>Ad.CHIT 9 0.106 84.7 </li></ul><ul><li>G1-3 10 0.071 57.1 </li></ul><ul><li>Coag.Time 11 0.029 23.5 </li></ul><ul><li>Lymph.% 12 0.029 23.2 </li></ul><ul><ul><li>Factor Rank Error Ratio </li></ul></ul><ul><li>Thr.tot 13 0.023 18.2 </li></ul><ul><li>Rest Nitrogens 14 0.019 15.2 </li></ul><ul><li>Haem.Time 15 0.007 5.6 </li></ul><ul><li>ESS 16 0.005 3.8 </li></ul><ul><li>Age 17 0.003 2.6 </li></ul><ul><li>Weight 18 0.003 2.5 </li></ul><ul><li>Chlorides 19 0.002 1.9 </li></ul><ul><li>D 20 0.002 1.8 </li></ul><ul><li>St.Neutr.tot 21 0.002 1.6 </li></ul><ul><li>Protein 22 0.002 1.5 </li></ul><ul><li>L/CC 23 0.002 1.4 </li></ul><ul><li>Erythrocytes 24 0.002 1.4 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

25.
Results of Bootstrap Simulation in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Number of Samples=3333 </li></ul><ul><li>Significant Factors Rank Kendall’s Tau-A P< </li></ul><ul><li>LIT 1 0.316 0.000 </li></ul><ul><li>D 2 -0.196 0.000 </li></ul><ul><li>P1-4 3 -0.189 0.000 </li></ul><ul><li>Leucocytes/CC 4 0.188 0.000 </li></ul><ul><li>HC/CC 5 0.187 0.000 </li></ul><ul><li>Erythrocytes/CC 6 0.186 0.000 </li></ul><ul><li>Lymphocytes/CC 7 0.185 0.000 </li></ul><ul><li>T1-4 8 -0.184 0.000 </li></ul><ul><li>N0-3 9 -0.176 0.000 </li></ul><ul><li>Seg.Neutrophils/CC 10 0.167 0.000 </li></ul><ul><li>Thrombocytes/CC 11 0.160 0.000 </li></ul><ul><li>Monocytes/CC 12 0.146 0.000 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

26.
Results of Bootstrap Simulation in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Number of Samples=3333 </li></ul><ul><li>Significant Factors Rank Kendall’s Tau-A P< </li></ul><ul><li>Eosinophils/CC 13 0.124 0.000 </li></ul><ul><li>Operation Type 14 -0.119 0.000 </li></ul><ul><li>G1-3 15 -0.119 0.000 </li></ul><ul><li>Histology 16 -0.118 0.000 </li></ul><ul><li>Chlorides 17 0.106 0.000 </li></ul><ul><li>Coagulation Time 18 -0.096 0.000 </li></ul><ul><li>Growth 19 -0.092 0.000 </li></ul><ul><li>Stick Neutrophils/CC 20 0.068 0.000 </li></ul><ul><li>Protein 21 0.063 0.000 </li></ul><ul><li>Combined Operation 22 0.048 0.000 </li></ul><ul><li>Rest Nitrogens 23 0.042 0.001 </li></ul><ul><li>Colour Index 24 0.041 0.000 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

27.
Results of Bootstrap Simulation in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Number of Samples=3333 </li></ul><ul><li>Significant Factors Rank Kendall’s Tau-A P< </li></ul><ul><li>ESS 25 0.038 0.002 </li></ul><ul><li>Erythrocytes tot 26 0.038 0.002 </li></ul><ul><li>Thrombocytes 27 -0.033 0.005 </li></ul><ul><li>Adjuvant CHIT 28 0.031 0.005 </li></ul><ul><li>Eosinophils tot 29 0.028 0.018 </li></ul><ul><li>Leucocytes tot 30 0.027 0.023 </li></ul><ul><li>Sex 31 0.027 0.023 </li></ul><ul><li>Weight 32 0.026 0.024 </li></ul><ul><li>Haemorrhage Time 33 0.026 0.024 </li></ul><ul><li>Monocytes tot 34 0.024 0.05 </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

28.
Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) <ul><li>Classification of Cases by Logistic Regression, n=150, Odds Ratio=86.7 </li></ul><ul><li>Observed Pred.Losses Pred.Survivors Correct </li></ul><ul><li>Losses 102 4 96.2% </li></ul><ul><li>5-Year Survivors 10 34 77.3% </li></ul><ul><li>Total 112 38 90.7% </li></ul><ul><li>Classification of Cases by Discriminant Analysis, n=150 </li></ul><ul><li>Observed Pred.Losses Pred.Survivors Correct </li></ul><ul><li>Losses 105 1 99.1% </li></ul><ul><li>5-Year Survivors 5 39 88.6% </li></ul><ul><li>Total 110 44 96 .0% </li></ul><ul><li>Classification of Cases by Neural Networks, n=150, Errors=0.0012 </li></ul><ul><li>Observed Pred.Losses Pred.Survivors Correct </li></ul><ul><li>Losses 106 0 100% </li></ul><ul><li>5-Year Survivors 0 44 100% </li></ul><ul><li>Total 106 44 100 % </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

29.
Ratio of Lymphocytes to Cancer Cells & Glucose Level in Prediction of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies (n=150 ) The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

30.
Prognostic SEPATH-Model of Cardioesophageal Cancer Patients Survival after Complete Esophagogastrectomies, n=150 The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

31.
Holling-Tenner Models of Cardioesophageal Cancer Cell Population and Cytotoxic Cell Population Dynamics

32.
Cardioesophageal Cancer Dynamics

33.
Conclusions: <ul><li>5-year survival and life span of cardioesophageal cancer patients after complete esophagogastrectomies significantly depended on: </li></ul><ul><li>1) cell ratio factors: ratio of cancer cell population to blood cell subpopulations in integral patient organism; </li></ul><ul><li>2) cancer characteristics (cancer cell population number, TNMG-system); </li></ul><ul><li>3) the data of blood cell circuit, biochemical homeostasis and hemostasis system; </li></ul><ul><li>4) character of surgical procedure; </li></ul><ul><li>5) anthropometric data. </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

34.
Conclusions: <ul><li>Optimal treatment strategies for cardioesophageal cancer patients are: </li></ul><ul><li>1) screening and early detection of cardioesophageal cancer; </li></ul><ul><li>2) availability of very experienced surgeons because of complexity of radical procedures; </li></ul><ul><li>3) aggressive en block surgery for completeness; </li></ul><ul><li>4) precise prediction; </li></ul><ul><li>5) adjuvant chemioimmunotherapy for patients with </li></ul><ul><li>unfavorable prognosis. </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA

35.
Address: Oleg Kshivets M.D., Ph.D., Consultant Thoracic, Abdominal, General Surgeon & Surgical Oncologist <ul><li>Surgery Department, Siauliai Public Hospital & Cancer Center </li></ul><ul><li>Tilzes:42-16, LT78206 Siauliai, Lithuania </li></ul><ul><li>Tel. 37041-416614 </li></ul><ul><li>e-mail: kshivets@yahoo.com </li></ul><ul><li>http//:myprofile.cos.com/Kshivets </li></ul>The 60 th Annual Meeting of Society of Surgical Oncology March 15-18, 2007, Washington , DC, the USA