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Kshivets O. Expert Systems for Diagnosis and Prognosis of Malignant Neoplasms
Kshivets Oleg M. Expert Systems of Diagnosis and Prognosis of Malignant Neoplasms 14.00.14-Oncology Author’s abstract of a dissertation submitted for the degree of the Doctor of Medical Sciences Omsk 1995 The research is done in Omsk Cancer Center (Omsk Oblast Oncologic Dispensary), Scientific-Research Institute of Oncol-ogy in Tomsk Scientific Center of Academy of Medical Sciences of Russia and the Prof. N.N.Petrov Research Institute ofOncology of Ministry of Health and Medical Industry of Russia, St.Petersburg. Scientific consultants:Academician of Russian Academy of Medical Sciences, Doctor of Medical Sciences, Professor B.N.Zirjanow, M.D., Ph.D.;Doctor of Medical Sciences, Professor V.M.Merabishvily, M.D., Ph.D.;Academician of Russian Academy of Sciences, Doctor of Technical Sciences, Professor D.A.Pospelov, Ph.D. Official Opponents:Doctor of Medical Sciences, V.I.Tichonov, M.D., Ph.D.;Doctor of Medical Sciences V.S.Sijanov, M.D., Ph.D.;Doctor of Physical-Mathematical Sciences V.P.Kuznetsov, Ph.D. Leading Institution:Moscow the P.A.Hertzen Scientific-Research Oncological Institute of Ministry of Health and Medical Industry of Russia,Moscow.Defense of the dissertation will be on June 15.1995 at 12 o’clock during the meeting of the Dissertation Council D.001.34.01in Scientific-Research Institute of Oncology in Tomsk Scientific Center of Academy of Medical Sciences of Russia (634050,Tomsk, per.Cooperativni,5). The dissertation is available in the library of Scientific-Research Institute of Oncology in Tomsk Scientific Center of Acad-emy of Medical Sciences of Russia (634050, Tomsk, per.Cooperativni,5). The author’s abstract is distributed on May 10.1995. Scientific Secretary of the Dissertation Council Dr. N.D.Kiseljova, M.D., Ph.D. The actuality of the problem. The problem of malignant neoplasm is not solved yet. According to the forecasts of theexperts of the WHO cancer will become the most spreading decease in the world in the 21st century and in 2015 15% thetotal mortality causes will be due to cancer (in 1992 it was only 10%) [Maurice I.,1992]. Nowadays over 80% of malignantneoplasm of the visceral localization are detected at the final stage. The oncopathology mortality in the economically devel-oped countries reached 22.5% from the total lethality [Debruyne F.M.,1991]. The success in anti-cancer struggle in opinionof the majority of oncologist is too modest in spite of the many billions dollars annual assignations for oncoscreening inves-tigation in all the highly developed countries of the world without any exception [Zajicek G.,1991]. This is clearly demon-strated by the results of the treatment process: The average of 60-80% of all the oncopatients die due to the generalizationand the relapses of the decease during the first 5 years after treatment, but the total 5-year survival rate of patients with theaggressive tumors like lung cancer (LC) and gastric cancer (GC) taking the first and the second places to the spreading on theEarth in Russia, the USA, Germany, France and other countries exceeds not more than 13-16% [Merabishvili V.M.,1991;Dvoirin V.V., Aksel E.M.,1992; Kshivets O.M.,1992; Sridhar K.S., Raub W.,1991]. To our deep regret there are no relevantscreening programs of LC and GC: The fluorography screening of LC demonstrates complete inconsistency and it is not usedin such countries as the USA, Canada and others but endoscopic screening of GC is also not used except for Japan becauseof astronomic expenses and incomparable resulting organizational outlay [Kshivets O., 1992; Lemarie E.,1991; Fontana R.S.,Sanderson D.R., Woolner L.B.,1991; Castonguay A., 1992; Mulschine I.L.,1992; Tamura K.,1993]. Now the leading European, American and Japanese experts have placed some hopes on the two oncoscreening programs,which have already showed their resultiveness: The mammography screening of breast cancer (BC) and cytological screen-ing of cervical cancer (CC) [Sagaidack V.N.,1992; Semiglazov V.F.,1992; Chu K.C., Kramer B.S.,1991; Geirsson G.,1992;Lopez V.G.,1992; Yanagawa H., 1992; Clark S.,1993; Lamarque I.L.,1993; Noda K.,1993]. The outcome of the existingoncoscreening programs is about 0.03-0.05% while 27-64% of early oncopathology is missed in spite of the astronomic fi-nancial expenses (screening detection of one patient with an early stage of BC costs about $20,000; CC - $100,000; GC -$42,000; colorectal cancer is $70,000). But in spite of the huge expenses the screening of malignant neoplasm of any local-
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 2ization allows not only to save patient’s lives but also to increase economic effectiveness of the spent money, as the existingscreening programs are less expensive than combined and complex treatment of oncopatients with less efficient therapy out-come. Even in Russia in spite of the lowest cost of medical examination and treatment the direct economic profit of detectionof one oncopatient having the first stage is 7-33 thousand dollars depending on the process localization [Chissov V.I., Starin-sky V.V., Borisov V.I.,1991]. So the early diagnostics allows even now to increase the 5-year survival rate of the oncopatients by several times while thecombined and complex treatment - only by 15-30% with incomparable financial expenses. That is why oncoscreening pro-grams dominate in the long-term strategic anti-cancer programs in the USA, Japan, Western Europe and Russia, that is whytens billions dollars are assigned on these programs, and that is why the supermodern high technologies are tested here. Differential diagnosis of malignant neoplasm is another very complicated branch of clinical oncology. In this sphere thereare more illusions, disappointments and failures than real results. That is why the great number of oncopatients is treated inthe usual hospitals for somatic and pre-cancer pathology while these patients are observed by different specialist for manyyears. It is found that in Russia the average of 75% of patients with LC, GC, CC and colorectal cancer visit doctors 8 timesduring the two years before oncopathology detection, but in the USA, where every patient was examined, 50% of early can-cer is not recognized in time in spite of an excellent diagnostic, endoscopic and computer technique [Gritsman Yu.Ya.,1981;Kshivets O.M.,1992; Chissov V.I., Trachtenberg A.H.,1993]. It means that the fate of the oncopatient depends on the firstvisit to a doctor and if the last is not competent enough, the future of the person is very tragic. On the other hand, a generalpractitioner usually meets 20-60 or more patients per day, spending 5-40 minutes per each and mostly diagnosing acute de-cease but oncopathology detection is uncommon during these hours. And we must not forget that there are no reliable earlycancer tests nowadays. In the real clinical trials all the patients being examined in policlinic or in hospital owing to the prac-tical impossibility carry out all oncodiagnostic methods that are expensive in a way (fibrogastroscopy costs up to $150 perone examination, fibrocolonoscopy - $500, computed tomography - $300, magnetic resonance imaging - $800, mammogra-phy - $100, even hemocculttest is $15-20 while these prices don’t include doctor’s services) [Ransohoff D.F.,1991; LangC.A.,1991; Fugarolas G.M.,1992]. So it is obviously necessity to take actions maximally reducing the number of patientstested for oncopathology within the reasonable limits. Unfortunately there is no program of this kind in the world. The third very complicated problem is to sharp estimate the expansion of the tumor process for the detected oncopatients.In fact, it is metastasizing of malignant neoplasm which is the main problem of clinical oncology, as almost all the failures ofsurgical, combined and complex treatment of cancer patients (up to 70-80%) are due to tumor metastases [BlochinN.N.,1981; Achmedov B.P.,1984]. The primary tumor is usually possible to excise but unfortunately there are so-called re-sidual “subclinical” metastases, which are not recognize due to the limited possibilities of modern visualizing methods ofdiagnosis. From this it follows that there are insistent requirement of the reliable programs for oncopathology staging and foraccurate identification of regional and distant metastases. The fourth quite important and unsolved problem is the reliable forecasting of survival rate of oncopatients. As a matter offact, the only radical method of treatment of the majority of cancer localization giving the chances for recovery is surgicalremoval of tumor and its metastases in spite of quite intensive researches developed during the last years in terms of chemo-therapy, immunotherapy, hormonotherapy and irradiation. Unfortunately the effectiveness of radical surgical managementhas already reached its limit and leaves much to be desired: The average real 5-year survival rate of the radically operatedoncopatients even after combined and extended removal is 30-35% and practically is not improved during last 40-50 years,as the majority of the patients have already advanced cancer [Chissov V.I.,1989; Kshivets O.M.,1991; Kinne D.W.,1991;Nazarian H.K., Giuliano A.E.,1993]. Usually up to 70-80% radically operated patients with any visceral cancer die duringthe first two years from relapses and generalization of the process. Unfortunately, there are not any methods determiningwith high-precision the favorable or unfavorable decease’s prognosis. If in case of the first and the fourth stages everything israther clearly: In the first case the favorable outcome will be in 90-100% (after radical removal of the tumor) and in the sec-ond case the unfavorable result will be with the same probability, then for the second and the third stages of cancer there is adilemma whether to treat the radically operated patient using adjuvant management (polychemo-, immuno-, hormonotherapyor irradiation) for increasing the 5-year survival rate. Nowadays this problem is easy to be solved: Practically all the radicallyoperated patients with the second or with the third stage of malignant neoplasm are treated using combined and complexmethods, which are very aggressive and extremely expensive (the estimation of the American experts state that the accurateselection of patients with the favorable decease’s prognosis will save 500 thousand dollars per one oncopatient)[MansourE.G.,1992]. Now the valid evaluation of immune homeostasis of cancer patient is paid much attention. It is connected with the numberof discoveries in oncoimmunology during the last decades (for example, it is found that precisely immune system plays themain role in the anti-tumor protection of human’s organism; the state of immune system influences on the dynamics of tumorcells population and in a case of the cell-bound immunity dysfunction causes the quick generalization of the process, etc.)[Kshivets O.M.,1981-1993; Boukovskaja S.N.,1982; Gorodilova V.V.,1983; Halpern I.,1988; Hirayama R.,1989; Van KesselK.,1990]. Nevertheless, the real effectiveness of oncoimmunology applications is disappointing and the real resulting of theexisting methods in immunodiagnosis and immunostaging of the oncopathology is very modest. So, at the modern phase of the oncology development the main methods of direct improvement of the cancer treatment out-come at the reasonable cost are, on the one hand, high-speed and high-precision recognition of oncopathology (early, differ-
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 3ential, corrected diagnosis, immunodiagnosis and immunostaging) and, on the other hand, exact prognosis for treated pa-tient’s survival. At the same time oncology is considered to be one of the most complex branches of medicine. It is character-ized by extreme number of theoretical, experimental and clinical researches with very modest real results. The peculiarity ofclinical oncology is also characterized by a great number of fuzzy, controversial, incomplete and unreliable informationquickly and constantly renewed. Perhaps no field of science can compete with the clinical oncology in complexity. If theextreme complexity of human’s homeostasis and oncopathology itself is taken into consideration, the doctor’s practice, hisclinical decisions are made in very difficult conditions with very limited laboratory-instrument and informatics possibilities.In this sense the symbiosis of technologies of knowledge engineering, expert systems, system analysis, simulation modeling,biometrics and computers make possible to increase multiply the effectiveness of doctor’s practice, especially in cancer diag-nosis and prognosis. The purpose and the objects of the research. The purpose of the dissertation is to optimize the stages of diagnosis-treatment process (DTP) using both traditional (statistical and biometric) and newest approaches (the theory of artificial intel-ligence, complex system analysis, simulation modeling, prognostics, the theory of optimal solution, evoinformatics, expertsystem technology, etc.) oriented to computers. The objects of the research are: 3.1. To develop methodology for high-precision early, differential and corrected diagnosis of malignant neoplasm based on the traditional blood tests, anthropometric, clinical and statistical data. 3.2. To create methodology for high-reliable prognosis of oncopatient’s survival rate taking into consideration the homeo- stasis parameters and tumor characteristics. 3.3. To develop methodology for accurate immunodiagnosis and immunostaging of malignant neoplasm. The scientific novelty of the research. For the first time five methodologies of diagnosis and prognosis of any oncopa-thology oriented for general practitioner of any level and for any conditions and optimizing all the steps of DTP in oncologywere developed: 1) technology of reliable high-speed and high-precision oncoscreening (SUPERONCOSCREENING-1.0: SOS-1.0) covering 99% of malignant neoplasm in terms of occurrence including those not having any screening programs; 2) technology of highly accurate differential diagnosis of malignant neoplasm (SUPERONCODIAGNOSIS-1.0: SOD-1.0) making possible to differentiate any oncopathology from any even serious non-specific pathology; 3) technology of high-precision corrected diagnosis of malignant neoplasm (SUPERONCODIAGNOSIS OF ME- TASTASIZING-1.0: SODM-1.0) making possible quite accurate estimation of the tumor spreading and subclinical generalization of the process; 4) technology of highly reliable and high-precision prognosis of oncopatient’s survival (SUPERONCOPROGNOSIS- 1.0 - SOP-1.0), including not only qualitative but also quantitative postponed prognosis of the decease (with the ac- curacy of up to one day); 5) technology of complex evaluation of immune homeostasis of the patients with malignant neoplasm (SUPERON- COIMMUNOLOGY-1.0: SOI-1.0). All these basic methodologies have no analogs in the world, are based on the knowledge engineering, complex systemanalysis, simulation modeling and are oriented for expert system’s technology and computers (from beginning PC to endsupercomputers). The resulting and accuracy of developed methods exceeds any existing cancer diagnostics and prognostics. Theoretical significance of the research. It is newly established fact that the patients with any malignant neoplasm at thefirst and second stages have stereotypical and certain changes in hematological, biochemical and immunological parametersand their ratio which correlates to the tumor cells quantity in integral organism. It is found that the system “cancer-patient’shomeostasis” consecutively passes through three phase transitions: “norm-oncobackground”, “oncobackground-early onco-pathology” and “early oncopathology-invasive cancer”. The transition of early oncopathology into invasive cancer resultsfrom the critical for a human level of 4.189e+9 tumor cell population. Above this level the cancer aggressiveness and de-cease’s prognosis are qualitatively changing. It also discovered the tumor dynamics is strictly regulated by the ratio of cancercell population quantity to the total quantity of normal cell population, blood cell subpopulations and immunocompetent cellsin the integral patient’s organism. Using the complex system analysis the whole spectrum of linear and non-linear dependen-cies and complex relationships between a tumor and hematological, biochemical and immunological data not described be-fore. It is proved that the 5-year survival rate of radically operated oncopatients positively depends on both homeostasis pa-rameters and tumor characteristics. A number of features characterizing regional and distant cancer metastasizing in the pa-tient’s organism homeostasis is detected. Complex dependencies of the survival rate of the patients having unfavorable de-cease’s prognosis are calculated and identified. Immunological parameters regulating the spreading of any oncopatology areestablished. Using the system analysis, simulation modeling, knowledge engineering, heuristic and biometric methods theauthor developed a number of diagnostic and prognostic indexes for high-precision early, differential, corrected diagnosis,immunodiagnosis and immunostaging of malignant neoplasm and for exact prognosis of postponed survival for every con-crete patient. Practical value of the research. A number of principally new reliable methodology in terms of expert system’s technol-ogy for highly accurate screening, differential, corrected diagnosis, immunodiagnosis and immunostaging of malignant neo-plasm of any localization; and for prognosis of oncopatient’s survival are developed. These methods may be used by any
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 4general practitioner or oncologist and are possible to use at any level in any country. The created basic programs make it pos-sible to reduce the volume of traditional and very expensive instrumental methods of testing; to increase multiply the detec-tion of early oncopathology practically of any localization, to improve the accuracy of tumor spreading determination, torecognize subclinical generalization, to select patients for combined and complex treatment and to save funds (costs are re-duced by 2-3 orders) with the incomparable effectiveness of the DTP. Publications. 45 scientific works covering the theme of the dissertation are published including 6 methodological recom-mendations, 15 patents submitted to the Scientific-Research Institute of State Patent Expertise of Russian Federation. Thesis Approval. 20 reports on the thesis were done during scientific, scientific-technical Russian and InternationalSymposiums and Conferences. The dissertation was discussed during scientific conferences in the Prof. N.N.Petrov Re-search Institute of Oncology of Ministry of Health and Medical Industry of Russia (St.Petersburg, 1993), in the AcademicianN.N.Blochin Union Cancer Research Center of Academy of Medical Sciences of Russia (Moscow, 1994) and in Scientific-Research Institute of Oncology of Tomsk Scientific Center of Academy of Medical Sciences of Russia (Tomsk, 1995). Volume and Structure of the dissertation. The dissertation has 486 pages of printed text and consists of introduction, 5chapters, conclusion, deductions, bibliography and supplements. The thesis is illustrated by 134 drawings, 185 tables and 153supplements. Bibliography includes 650 origins (273 - Russian and 377 - foreign ones). Materials and Methods of the Research To fulfill the task of the present research in terms of early and differential diagnosis data of the 12162 patients with malig-nant neoplasm of different localization with morphologically verified diagnosis, patients having pre-cancer and non-malignant pathology, practically healthy people having been checked in policlinic and hospitals and treated in Omsk CancerCenter in 1969-1994 (see Table N1, “The structure of control and learning retrievals of patients). Table N1. The Structure of Control and Learning Samplings of Patients NN SAMPLINGS QUANTITY 1 Early and differential oncodiagnosis and immunooncodiagnosis 12162 2 Corrected oncodiagnosis and immunooncodiagnosis 6013 3 Immunodiagnosis and immunostaging of malignancy 1743 4 Prognosis of survival rate of oncopatients 1429 LOCALIZATIONS (CONTROL) 3509 Oncopatients 2442 1 Gastric cancer patients with I-IV stages, T1-3N0-2M0-1 1461 2 Lung cancer patients with I-IV stages, T1-3N0-2M0-1 901 3 Gastric cancer patients with I-IV stages, T1-3N0-2M0-1 1461 4 Cervical, endometrial cancer patients with I stage, T1-2N0M0 80 Old patients with pre-cancer or nonmalignant pathology 852 1 Patients with pre-cancer gastric pathology 416 2 Patients with nonmalignant lung pathology 356 3 Patients with pre-cancer pathology of genitals 80 4 Practically healthy old people 215 A EARLY AND DIFFERENTIAL ONCODIAGNOSIS (CONTROL) 1961 Oncopatients 1297 1 Gastric cancer patients with I stage, T1-2N0M0 123 2 Gastric cancer patients with I-IV stages, T1-3N0-2M0-1 655 3 Lung cancer patients with I stage, T1-2N0M0 80 4 Lung cancer patients with I-IV stages, T1-3N0-2M0-1 359 5 Cervical, endometrial cancer patients with I stage, T1-2N0M0 80 Old patients with pre-cancer and nonmalignant pathology 544 1 Patients with pre-cancer gastric pathology 243 1.1 Patients with chronic atrophic gastritis 76 1.2 Patients with gastric adenomatous polyps 87 1.3 Patients with callous gastric ulcer 80 2 Patients with nonmalignant lung pathology 221 2.1 Patients with pulmonary benign tumors 53 2.2 Patients with chronic pulmonary abscess 54 2.3 Patients with pulmonary tuberculoma 34 2.4 Patients with chronic pneumonia or pneumosclerosis 80
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 5 3 Patients with pre-cancer pathology of genitals 80 4 Practically healthy old people 120 B EARLY AND DIFFERENTIAL ONCODIAGNOSIS (LEARNING) 8653 1 Oncopatients (all localizations) 4279 2 Old patients with pre-cancer and nonmalignant pathology 3125 3 Practically healthy old people 1249 C CORRECTED ONCODIAGNOSIS, STAGING (CONTROL) 1014 1 Gastric cancer patients with I-IV stages, T1-3N0-2M0-1 655 2 Lung cancer patients with I-IV stages, T1-3N0-2M0-1 359 D CORRECTED ONCODIAGNOSIS (LEARNING) 4279 1 Oncopatients with I-IV stages (T1-4N0-2M0-1) (all localizations) 4279 E PROGNOSIS OF MALIGNANCIES (CONTROL) 708 1 Gastric cancer patients with II-III stages, T1-3N0-2M0 347 1.1 Gastric cancer patients with II-III stages, T1-3N0-2M0 (more 5 years) 131 1.2 Gastric cancer patients with II-III stages, T1-3N0-2M0 (less 5 years) 216 2 Lung cancer patients with II-III stages, T1-3N0-2M0 158 2.1 Lung cancer patients with II-III stages, T1-3N0-2M0 (more 5 years) 73 2.2 Lung cancer patients with II-III stages, T1-3N0-2M0 (less 5 years) 85 1.3 Gastric cancer patients with IV stage, T1-3N0-2M1 131 2.3 Lung cancer patients with IV stage, T1-3N0-2M1 72 F PROGNOSIS OF MALIGNANCIES (LEARNING) 721 1 Oncopatients with I-IV stages (T1-4N0-2M0-1) (all localizations) 721 G IMMUNODIAGNOSIS OF MALIGNANCIES (CONTROL) 840 1 Oncopatients with I-IV stages, T1-3N0-2M0-1 437 1.1 Gastric cancer patients with I-IV stages, T1-3No-2M0-1 205 1.2 Lung cancer patients with I-IV stages, T1-3N0-2M0-1 232 2 Old patients with pre-cancer and nonmalignant pathology 308 2.1 Patients with pre-cancer gastric pathology 173 2.2 Patients with nonmalignant pulmonary pathology 135 3 Practically healthy old people 95 H IMMUNODIAGNOSIS OF MALIGNANCIES (LEARNING) 903 1 Oncopatients (all localizations) 547 2 Old patients with pre-cancer and nonmalignant pathology 293 3 Practically healthy old people 63 In terms of corrected diagnosis the information on the 6013 oncopatients was analyzed; in terms of immunodiagnosis andimmunostaging - the 1743 patients with malignant neoplasm, pre-cancer and non-malignant decease and healthy donors; interms of prognosis - the 1429 patients with oncopathology of some localization having been operated in the clinic in 1970-1990. The basis for developed basic technologies of diagnosis and prognosis of malignant neoplasm is the data of the 3509patients (over 1500 parameters per every patient), checked and treated and been under control in Omsk Cancer Center in1969-1994. Later the methods of screening and differential diagnosis were tested on the 8653 patients with cancer of differ-ent localization, pre-cancer and non-malignant pathology and practically healthy persons. The technology of differential di-agnosis was proved on the learning retrieval of the 4279 operated and morphologically verified oncopatients. This groupincluded the 2442 oncopatients operated on GC (1461 patients), LC (901 patients), CC and endometrial cancer (EC) (80patients). The diagnosis and the stage of decease were established on the basis of intraoperational samples and after the thor-ough hystologic investigation of removal organs, tissue, lymphatic nodes and biopsy material. The control group included thepatients with pre-cancer gastric pathology (416 patients), patients operated on non-malignancy of lung (356 patients), womenoperated on pre-cancer pathology of genitals (80 patients) and practically healthy old people (215 persons). All the peoplefrom the control groups were checked and operated in the clinic for suspicion of oncopathology. All the patients had pre-operation examination including peripheral blood count, biochemical tests of venous blood using usual unified methods,clinical, anthropometric, X-ray examination, endoscopy and sonography, electrocardiography and also doctor’s examination,if required, computed tomography and radioisotope scanning. After operations the data of intraoperational investigation, information on the character, volume and radicality of surgery,all intraoperational and postoperational complications, anatomic and morphologic characteristics of tumor (size and volumeand the character of tumor growth, infiltration of tumor into adjacent organs, regional and distant metastases, histology,
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 6TNMG-classification, etc.): totally over 1500 nominal, logic and quantitative factors for every patient were registrated. Allthe patients are monitored in postponed period including 1994. The 1244 GC patients (GCP) and LC patients (LCP) of I-IV stages operated in the clinic during 1970-1990 became theobject for development of prognosis technology in terms of clinical oncology. All of them were monitored in postponed pe-riod: the time and cause of death (because of relapses, generalization or somatic pathology) were fixed and also the life dura-tion after operation was calculated with the accuracy of one day. The patients with the first stage of cancer, patients with le-thal operation outcome, patients being observed after radical operation less than 5 years are excluded from the total sampling.708 patients having the II-IV stages of oncopathology were included into the group to be studied. 505 oncopatients with II-III stages have been radically operated: 347 GCP and 158 LCP. 204 of them have lived more than 5 years without any fea-tures of the process progressing: 131 GCP and 73 LCP. 301 patients died because of relapses and generalization of cancerduring the first 5 years after radical operation: 216 GCP and 85 LCP. Explorative and palliative surgical treatment was per-formed for the 203 patients having the IV stage of the decease: 131 GCP and 72 LCP. The developed technology of progno-sis was verified on a group of the 721 operated patients with I-IV stages of different malignant neoplasm having been moni-tored in postponed period. The initial data for the development of programs of immunodiagnosis and immunostaging of oncopathology were the re-sults of immunological testing of the 840 patients: 205 GCP, 232 LCP, 173 patients with pre-cancer gastric pathology, the135 patients with non-malignant lung pathology and the 95 practically healthy donors. Later the technologies of immunodi-agnosis and immunostaging was tested on the 903 patients with malignant neoplasm of the I-IV stages of different localiza-tion, people with pre-cancer and non-malignant decease and healthy donors. The representativeness of all samplings was reached by means of the randomization based on the unrepeated random selec-tion. All the data were input in database management system PARADOX and was operated on the spreadsheets QUATTROPRO, LOTUS 1-2-3, intellectual program-algorithmic complexes CLASS-MASTER, SANI and instrumental expert systemINTEX for PC IBM AT/286. To meet the demands of early and differential oncodiagnosis the hematological and biochemical parameters of 4 groups ofpatient’s homeostasis were analyzed: 123 GCP of the I-II stages; 160 LCP, CC patients (CCP) and EC patients (ECP) of theI-II stages; 655 GCP of the I-IV stages; 359 LCP of the I-IV stages operated in the clinic in 1969-1994. The patients withpre-cancer gastric pathology (n=243), with non-malignant lung pathology and with pre-cancer genitals decease (n=160) and120 practically healthy old people operated for lipoma, atheroma and hernia were included in the control group. The certaintyof distinctions was verified by t-distribution of Student, Pirsons, Kramers, Chuprov’s and directed connection’s coefficients χ 2and also -criterion. There were also used multiple correspondence analysis and multi-factor clustering in the modifica-tions of Aivazyan, Buhshtaber, Yenukov and Meshalkin. Some of the results are presented in the table N2 (“Early diagnosisof malignant neoplasm”) and table N3 (“Differential diagnosis of malignant neoplasm”). When analyzing the above-citedmaterial it is necessary to pay attention to the stereotypical and universal character of changes in the studied parameters ofhomeostasis at 4 totally different localization’s cancers with absolutely different clinical symptoms and morphology by com-parison with the pre-cancer, non-malignant pathologies and norm. The probability of the random coincidence of these inves-tigation results in absolutely different representative and randomized samplings converges to zero here and contingency ofthis phenomenon is absolutely impossible in the living supercomplex systems. The question is on the regularity of discoveredphenomenon while such changes characterize the early oncopathology as well when the effectiveness of the treatment proc-ess tends to be 100%. It is obviously that the discovered certain changes in the hematological and biochemical homeostasisof patients with early cancer are connected with genome and cell circuit. In spite of the fact that blood is very stable medium,the simple using of the found dependencies in traditional blood tests is difficult due to variability of parameters and errors inmethods. Taking the above-cited facts into consideration and using complex system analysis, knowledge engineering, simu-lation modeling, biometric, statistic and heuristic methods the author developed a number of screening and differential diag-nosis tests based on usual routine blood count for the purposes of early and differential diagnosis of any malignant neoplasm.The advantage of these tests is their stability to methods errors and measurement errors (an error of hematological and bio-chemical data may reach 30-40% not influencing the effectiveness of oncoscreening and differential oncodiagnosis), highsensitivity, certainty and universality for any oncopathology (cancer, sarcoma, hemoblastos), reliability and stability to vari-ability of different blood data. The multiple correspondence analysis is presented in the stereotypical diagram dispersionbased on the developed indexes both for GCP of the I-II stages and LCP, CCP and ECP of the I-II stages by comparison withthe non-malignant pathology and norm; see figure N1 (“The results of multiple correspondence analysis of blood indexes ofthe IKD1-10 series of oncopatients, pre-cancer patients and healthy people”), where a) LCP, CCP and ECP of the I-II stages(n=160), patients with non-malignant lung pathology and pre-cancer genitals decease (n=160) and healthy people (n=120); b)GCP of the I-II stages (n=123), patients with pre-cancer pathology (n=243) and healthy people (n=120). The multi-factorcluster analysis of indexes of the IKD1-10 series of GCP, LCP, CCP and ECP of the I-II stages and those with invasive can-cer and patients from the control samplings made it possible the high-precision recognition patients with the early oncopa-thology and with the invasive cancer among patients with pre-cancer and non-malignant pathology; see some of the resultson figure N2 (“The results of multi-factor cluster analysis of diagnostic blood indexes of the IKD1-10 series according to thecriterion “cancer-non-malignant pathology” of LCP of the I-IV stages (n=359) and patients with non-malignant lung pathol-
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 7ogy (n=141): patients with abscesses, tubercolomas, non-malignant tumors”). This is demonstrated of the serviceability ofthe developed indexes both for early and differential diagnosis of malignant neoplasm practically of any localization. Theincontestable advantages of these diagnosis indexes are their accuracy, availability for any level of medical care and stabilityto the measurement errors. When multi-factor linear correlation-regression analyses and descrete multivariate analysis of interconnections of thehomeostasis parameters and tumor size has been realized for 1014 patients operated for GC (n=655) and LC (n=359) of the I-IV stages the uniqueness universal dependence was discovered between the quantity of tumor cells population and the num-ber of homeostasis parameters of patient’s organism (some of the results are presented in table N4: “Interdependencies be-tween the average tumor diameter and homeostasis parameters of oncopatients”). It means that homeostasis parameters canbe used in calculation tumor size; see figure N3 (“Estimation of the average malignant tumor diameter: a) in terms of SOD-1.0 and SODM-1.0 technologies; b) in terms of SOI-1.0 technology”). Using complex system analysis and simulation modeling in terms of synergetics using also the statements from theories ofHopf, Landau, Turing and Marchuk it is proved the validity author’s theory about phase transitions in the system “cancer-patient’s homeostasis”: 1) phase transition “norm-omcobackground”; 2) phase transition “oncobackground-early oncopa-thology”; 3) phase transition “early oncopathology- invasive cancer”. If the diagnosis of the first two phase transitions de-pends on the outcomes of early and differential oncodiagnosis, the identification of the third phase transition results in theeffectiveness of the treatment process and the future fate of the patient. It is also verified that the most important figure ofthis transition for human is the quantity of malignant cells population in the patient’s organism and the average criticalthreshold of this population is 4.189e+9 (the average tumor diameter is 2 cm.). Below such value there is a temporal dynamicequilibrium between the cancer and patient’s homeostasis and the 5-year survival rate of radically operated patients tends tobe 100%. The excess over this threshold results in fatal and irreversible consequences when the effectiveness of treatmentgoes down up to 10-15%; see figure N4 (“The dependence between life duration (days) of radically operated oncopatientsand the average tumor diameter, where M1=1cm., M2=2cm.: a) LCP of the II-III stages (n=158); b) GCP of the II-III stages(n=347)”). The present research studied the homeostasis parameters, typical for the two extreme states of this phase transition: earlyoncopathology and invasive cancer. The number of oncopatients was 1014 including patients operated for GC (n=655), LC(n=359) of the I-IV stages; see table N5 (“Interdependence between the homeostasis data, the tumor characteristics of pa-tients with malignant neoplasm and the phase transition of early oncopathology into invasive cancer”) and table N6 (“Inter-dependence between tumor, cell homeostasis data of patients with malignant neoplasm and phase transition of early cancerinto invasive cancer”), where Er.tot., L tot., Segm.tot., Lymph.tot., M tot. Throm.tot. - are the total populations of erythro-cytes, leukocytes, segmented neutrophils, lymphocytes, monocytes, thrombocytes in the blood of the oncopatient. As we seefrom the presented above-mentioned material, the great role in phase transition of early oncopathology into invasive cancerof any localization of the process is played by the quantity of malignant cells population (tumor of an average size), by theratio of the tumor cells to the total number of normal cells in the organism and to the total subpopulations of human bloodcells, as well by a number of homeostasis parameters and malignant neoplasm characteristics. The data of big sampling of 1014 operated oncopatients (655 GCP and 359 LCP of the I-IV stages) showed that during theprocess of distant and regional metastasizing the homeostasis parameters of the patients with any oncopathology are chang-ing on single scenario, while the development of metastases in regional lymphonodules and distant metastases are closelyinterdepended and strictly determined by the total population of malignant cells in the patient’s organism and also by cellfactors of the ratio; some of the results are given in table N7 (“Interdependence between homeostasis data, tumor characteris-tics of oncopatients and distant metastasizing”), table N8 (“Interdependence between tumor and cell homeostasis data of on-copatients and distant metastases”), table N9 (“Interdependence between homeostasis data of patients, cancer characteristicsand metastasizing in regional lymphonodules”), table N10 (“Interdependence between tumor and cell homeostasis character-istics of patients with metastasizing in regional lymphonoduses”) and figure N5: a) the results of multiple correspondenceanalysis of blood indexes of the IKM1-10 series of GCP (n=655) of the I-IV stages using criterion M0-M1; b) the results ofmulti-factor analysis of these patients. Taking into consideration the importance of distant and regional metastasizing for theoptimization of the treatment process in terms of oncology the author using the modern information technologies (knowledgeengineering, system analysis, simulation modeling) developed a number of indexes of the IKM1-10 and IKML1-3 serieswhich sufficiently reliable classify the regional and distant metastases of any oncopathology based on the homeostasis pa-rameters; see figure N5, figure N6 (“The results of multi-factor cluster analysis of diagnostic blood indexes of the IKM1-10and IKML1-3 series using criterion N0-N1-2 for GCP (n=655) of the I-IV stages: 229 GCP have no regional metastases N0and 426 GCP have metastases in regional lymphonoduses N1-2”), figure N7 (“The results of multi-factor cluster analysis ofdiagnostic blood indexes of the IKM1-10 and IKML1-3 series using criterion N0-N1-2 for LCP (n=359) of the I-IV stages:156 LCP have no regional metastases N0 and 203 LCP have metastases in regional lymphonodules N1-2”). When analyzing the survival rate of the 708 operated oncopatients (347 GCP and 158 LCP of the II-III stages; 131 GCPand 72 LCP of the IV stage) it is discovered that, firstly, the forecast of any malignant neoplasm is strictly determined byphase transition of early oncopathology into invasive cancer not depending on its localization; secondly, the 5-survival rateof radically operated oncopatients certainly depends on a number of both homeostasis parameters of the concrete patient andon the tumor characteristics, while this dependence is of universal and stereotypical character practically for any cancer;
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 8thirdly, behavior and aggressiveness of tumor and, consequently, the postponed decease prognosis are strongly regulated bythe ratio of malignant cells population quantity to the factors of cell homeostasis in the integral patient’s organism; some ofthe results are presented in table N11 (“Interdependence between homeostasis data and tumor characteristics of patients withmalignant neoplasm and the 5-year survival after radical operations”), table N12 (“Interdependence between homeostasisparameters and life duration of oncopatients died during the first 5 years after radical operations”), table N13 (“Interdepend-ence between homeostasis parameters and life duration of oncopatients with the IV stage of the process after non-radicaloperations”), figure N8 (“Interdependence between tumor’s characteristics and the 5-year survival rate of radically operatedpatients: a) 347 GCP of the II-III stages; b) 158 LCP of the II-III stages”), figure N9 (“The trajectories of interdependenciesbetween tumor’s characteristics and radically operated oncopatients lived more than 5 years after radically operation: a) 131GCP of the II-III stages; b) 73 LCP of the II-III stages”), figure N10 (“The trajectories of interdependencies between tumor’scharacteristics and radically operated oncopatients died from generalization of the process during the first 5 years after radi-cally operation: a) 216 GCP of the II-III stages; b) 85 LCP of the II-III stages”). A simple use of the found dependencies forprognosis is difficult due to variability of parameters and measurement errors. In view of importance of accurate prognosisfor treatment process the author developed prognostic indexes of the IKP1-10 and IKPU1-5 series for high-precision progno-sis of postponed survival rate and for reliable identification of people with unfavorable decease prognosis and estimate theirlife duration; see figure N11 (“The quantitative prognosis of survival rate of operated oncopatients: a) GCP and LCP of theII-III stages (n=301); b) GCP and LCP of the IV stage (n=203)”). Complex system analysis of immunological tests made for 437 patients with malignant neoplasm, 308 people with pre-cancer and non-malignant pathology, 95 healthy donors demonstrates that immune homeostasis is changing stereotypicallynot depending on the malignant neoplasm localization, while these changes of immunity correlate with the process spreadingand certainly differ from immune homeostasis of patients with pre-cancer and non-malignant pathology and of healthy peo-ple; some results are presented in table N14 (“Informativeness of the immune homeostasis data in early and differential diag-nosis of oncopathology: 50 GCP of the I-II stages and 173 patients with pre-cancer gastric pathology”), table N15 (“Informa-tiveness of the immune homeostasis data in early and differential diagnosis of oncopathology: 40 LCP of the I-II stages and135 patients with non-malignant gastric pathology”), table N16 (“Interdependencies between immune homeostasis parame-ters, indexes of the IKI1-10 series and the average diameter of the primary tumor of oncopatients: 205 GCP and 232 LCP ofthe I-IV stages”), table N17 (“Interdependencies between cell factors of the ratio in the system “cancer-immune homeostasisof patient” and the staging of malignant neoplasm: 205 GCP and 232 LCP of the I-IV stages”). The author developed diag-nostic indexes of the IKI1-10 series for the purposes of immunodiagnosis and immunostaging of any oncopathology allow-ing to recognize precisely patients with cancer of an early stage among the patients with pre-cancer and non-malignant pa-thology; see figure N12 (“The results of multi-factor cluster-analysis of immunodiagnosis indexes of the IKI1-10 series usingcriterion “cancer-pre-cancer pathology” for 205 GCP of the I-IV stages and for 173 people with pre-cancer gastric decease(gastric callosal ulcer and adenomatous polyps)”), figure N13 (“The results of multi-factor cluster-analysis of immunodiag-nosis indexes of the IKI1-10 series using criterion “cancer-pre-cancer pathology” for 232 LCP of the I-IV stages and for 135people with non-malignant lung decease (abscesses, tuberculomas and non-malignant tumors)”). Research Summary The found dependencies made it possible to develop 5 new strategically important original technologies oriented practi-cally for any doctor of any level and for all conditions to optimize qualitatively all the stages of DTP in terms of oncology:1) technology of total and high-precision oncoscreening (SOS-1.0) with the accuracy of up to 95% and detection of 99% of malignant neoplasm in terms of occurrence, while the recognition of oncopathology of all localization reaches 30%; see figure N14-1(“The structure of the “Superoncoscreening-1.0” system”);2) technology of high-precision differential diagnosis of any oncopathology (SOD-1.0) with the accuracy of up to 98%, while malignant neoplasm detection up to 80% which allows to differentiate oncopathology from any even serious non- specific pathology; see figure N14-2 (“The structure of the “Superoncodiagnosis-1.0” system”);3) technology of corrected diagnosis of malignancies (SODM-1.0) with the accuracy of up to 96% making it possible to detect the tumor spreading and subclinical generalization process reliably enough; see figure N14-3 (“The structure of the “Superoncodiagnostics Metastisizing-1.0” system”);4) technology of high-precision prognosis of oncopatient’s survival rate (SOP-1.0) with the accuracy of up to 85% allow- ing to make not only qualitative but also quantitative postponed prognosis of the decease (with the accuracy one day); see figure N15-4 (“The structure of the “Superoncoprognosis-1.0” system”);5) technology of immunodiagnosis and immunostaging of malignant neoplasm (SOI-1.) with the accuracy of up to 98% allowing to make highly accurate early, differential and corrected immunodiagnosis of any oncopathology using immu- nogram; see figure N15-5 (“The structure of the “Superoncoimmunology-1.0” system”). While developing these systems the author used both traditional approaches (biometrical and statistical methods) and newinformation methodologies (complex system analysis, theory of artificial intelligence, simulation modeling in terms of syner-getics, theory of optimal decisions, diacoptics, evoinformatics, interval statistical modeling, etc.). All the created programsare oriented on the technology of expert systems and computers and are designed for both general practitioners and profes-sional oncologists of any level and in any country. All the diagnosis process in terms of these technologies is aimed at active
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 9detecting of early oncopathology, when the patient’s recovery reaches 100% and consists of 3 steps, that is every patientmust pass through three-stage selection, at every stage the space of search is reduced and, consequently, the number of thepatient decreases by 2-3 orders; see figure N16 (“The main stages of the diagnosis process in terms of oncology”). At thefirst stage the total active screening of population in different regions is made when theoretically all the population of mil-lions of people is tested using SOS-technology. During this process the patients with suspicion of any oncopathology arechosen. In this group there will be patients with pre-cancer and non-malignant pathology. All of them must pass through nexttesting using SOD- and SODM-technologies (if there is an immunological laboratory - using SOI-technology), which willdifferentiate patients with any malignant neoplasm from any non-malignant pathology with the accuracy of up to 98% andthey will also identify the spreading of tumor process. All the 5 methodologies developed by the author are based on theusual and widely used in all countries blood tests. All the systems are oriented for a general practitioner. All the technologiesare easily automated, are very effective and extremely cheap (the cost of SOS-test using hematological flow cytometry ana-lyzers and computers will not exceed $0.20 per one test; SOD-, SODM,- SOP-test - $1; SOI-test - $10). Thanks to createdtechnologies any doctor of any country and any level will have at his disposal the powerful and available tool for highly ac-curate screening, differential and corrected diagnosis and also for prognosis of malignant neoplasm at reasonable cost, whilesuch tool is ready to use now, but not in the perspective some day. The developed methodologies make a good addition totraditional but unfortunately very expensive and laborious visual and morphological methods of oncodiagnosis. The great progress in the field of supermodern information technologies (superfast computers, optoelectronic communica-tions, information superhighway, high-precision measuring apparatus, expert and intellectual systems) creates the necessaryprerequisites for testing of the whole population ranging from new-born children to old people using screening, diagnosingand prognosing systems. Theoretically, using basic technologies any doctor nowadays can test any patient for any oncopa-thology in any time and then deal with somatic decease. Moreover any person making blood analyses can be tested himselfusing created systems for malignancies and get information by the telephone or computer network (Internet, information su-perhighway). Research Results and their Discussion The present research shows that the patients with malignant neoplasm of any location even on the first and second stageshave stereotypical and certain changes of hematological, biochemical, immunological parameters and their relationshipswhich correlates to the quantity of the tumor cells population in the organism, while these changes are detected even at earlyoncopathology when the effectiveness of the treatment process tends to be 100%. The data of hematological, biochemicaland immunological homeostasis of patients with an early oncopathology of any localization certainly differ from norm, pre-cancer and non-malignant pathology, that is homeostasis of a healthy person or a patient with any non-malignant pathologyprincipally distinguishes from the homeostasis of a patient with early cancer. These are the two absolutely different station-ary states: state of norm (somatic pathology) and state of oncobackground (early oncopathology), while this transition ofnorm into the state of oncobackground is realized spasmodically without intermediate states, that is a phase transition “norm-oncobackground”. This phenomenon, unknown before, makes it possible, in its turn, to real simultaneous screening of alllocalization’s oncopahology at once. Using complex system analysis and simulation modeling it is found that the system “cancer-patient’s homeostasis” passesthrough 3 phase transitions: norm-oncobackground, oncobackground-early oncopathology, early oncopathology-invasivecancer. The transition of early oncopathology into invasive cancer results from the critical for human level of 4.189e+9 tu-mor cells population. Above this level the tumor aggressiveness and decease prognosis are qualitatively changing. Below thislimit there is a temporally dynamic equilibrium between the cancer and the patient’s homeostasis, that is the last stationarystate when the total patient’s recovery is still possible. The excess over this threshold results in irreversible consequenceswhen the effectiveness of surgery and therapy, that is 5-year survival rate of the treated patients decreases up to 10-15%. It isdetected that phase transition of early oncopathology into invasive cancer strictly depends on a number of hematological,biochemical and immunological parameters of a patient’s homeostasis as well on a number of morphological criteria of ma-lignancy independing on the localization of the process. It is proved that early oncopathology and invasive cancer are the twototally different states not only from prognostic but also pathophysiologic and pathomorphologic points of view. It is discov-ered that a great role in phase transition of early oncopathology into invasive cancer is played by a malignant cells popula-tion’s quantity, the ratio of this quantity to total normal cell’s quantity in the integral patient’s organism, blood cells popula-tion’s quantity and immunocompetent cells quantity. A whole number of universal linear and non-linear relationships andcomplex interconnections between the tumor and hematological, biochemical and immunological data, unknown before. It is discovered that the process of regional and distant metastasizing of any cancer location is strictly determined by thetotal number of malignant cells population in the patient’s organism and depends on the ratio of cancer cells population’squantity to total population of healthy cells, blood cells and immunocompetent cells, that is the process of metastasizing arestrongly regulated by the parameters of patient’s cell homeostasis. Such factors as tumor differentiation degree, histologicstructure and tumor’s growth type make less influence on the metastasizing in spite of the traditional ideas. It is revealed that the prognosis of any malignancy strictly depends on phase transition of early oncopathology into invasivecancer independing on the process localization. It is proved that the 5-year survival rate of radically operated oncopatients isregulated significantly both by homeostasis parameters of the concrete patient and tumor’s characteristics, while this depend-
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 10ence is of a universal and stereotypical character practically for any oncopathology. It is also found that the behavior andaggressiveness of a tumor and, consequently, the postponed decease prognosis are strongly determined by the ratio of malig-nant cells population’s quantity to the factors of cell homeostasis in the integral human organism. It is proved that betweenthe life duration of radically operated patients with malignant neoplasm of the second and the third stages the whole numberof hematological and biochemical homeostasis data and tumor’s characteristics there is a net of complex, specific quantita-tive, nominal and logical dependencies. It is discovered that the life duration of radically operated patients with the unfavor-able decease outcome and patients is with the IV stage of cancer is regulated by the same factors of homeostasis and thequantity of tumor cells population in the whole patient’s organism not depending on the process localization. The complexdependencies of survival for oncopatients with unfavorable decease prognosis are calculated and identified. In spite of the fact that blood is extremely stable medium, a simple use of the discovered dependencies in traditional bloodtests and immunogram in terms of diagnosis and prognosis of malignancies is difficult due to variability of parameters andmethod’s errors. Taking the above facts into consideration and using system analysis, knowledge engineering, simulationmodeling, biometrics, statistic and heuristic methods the author developed the number of indexes for the purposes of screen-ing, differential and corrected diagnosis, immunodiagnosis, immunostaging and prognosis of any malignancy based on tradi-tional blood tests, immunogram and anthropometrical parameters. The advantage of them is stability to method’s errors andmeasurement errors (an error of hematological, biochemical and immunological data may reach 30-40% not influencing onthe effectiveness of DTP), high sensibility and certainty, universality for any oncopathology (cancer, sarcoma, hemoblastos),reliability and stability to variability of different blood data. Based on the found dependencies 5 new methodologies in terms of expert system technology for highly accurate diagnosisand prognosis of any malignancy oriented for any doctor and any level of medical care: SOS-1.0, SOD-1.0, SODM-1.0,SOP-1.0 and SOI-1.0 were developed. These systems do not have any analogs in the world. Conclusion 1. The present research which studied 12162 patients with malignant neoplasm, pre-cancer and non-malignant pathology of any localization and practically healthy people demonstrated that the parameters of hematological, biochemical and immunological homeostasis and their interconnections of patients with any early oncopathology are changing typi- cally, while these changes are certainly different from the norm, pre-cancer and non-malignant pathology and strictly correlate to the total quantity of malignant cell’s population in the patient’s organism and neoplasm’s prognosis. 2. The system analysis of data of 6013 oncopatients made it possible to establish that there is a complex net of stable re- lationship and interconnections between the hematological, biochemical, immunological homeostasis of a patient and a malignant tumor where factors of the ratio of total quantity of blood cell’s subpopulations, immunocompetent cells and healthy cell’s population to the total quantity of malignant cell’s population in the whole patient’s organism play the main and universal role. The dynamic behavior of the cancer and, in the end, the decease prognosis for the con- crete patient are depended on numerical values of this ratio. 3. Using complex system analysis and simulation modeling it is found that the system “cancer-patient’s homeostasis” passes through three phase transitions (norm-oncobackground, oncobackground-early oncopathology, early oncopa- thology-invasive cancer) in the process of which the qualitative characteristics, behavior and aggressiveness of the malignancy, anti-tumor abilities of the patient’s homeostasis and decease prognosis are changing spasmodically. 4. Phase transition of an early oncopathology into invasive cancer happens when the quantity of malignant cell’s popula- tion reaches 4.189+9 per human organism and the qualitative oncopathology prognosis gets worth. 5. The process of regional and distant metastasizing and the generalization of malignancy are typical, their dynamics is influenced by the same hematological, biochemical and immunological factors of human organism’s homeostasis, while these process are stringently interdepended, are of a phase character and are strictly determined by the ratio of total quantity of malignant cell’s population to the total quantity of healthy cells, blood cells and immunocompetent cells in the whole patient’s organism independing on the tumor localization. 6. Complex system analysis of the postponed survival rate of 1429 operated oncopatients revealed that prognosis of any malignancy for patient depends on phase transition of early oncopathology into invasive cancer and strictly deter- mined both by the homeostasis data and tumor’s characteristics, while the life duration of radically and non-radically operated oncopatients with the unfavorable decease prognosis practically does not depend on the process localization and is regulated by the same factors of homeostasis and oncopathology. 7. The 5-year survival rate of radically operated oncopatients certainly and strictly depends on a whole number of hematological, biochemical and immunological parameters of homeostasis; on cell factors of the ratio of tumor cells to normal cells for a single patient; on malignancy characteristics. This dependence is of a universal and stereotypical character at any oncopathology localization. 8. Complex system account of hematological, biochemical, immunological, anthropometrical, clinical, statistical and epi- demiological data in terms of expert systems technology allows the detection of malignancies of any localization up to 30% under screening and up to 80% under differential diagnosis and immunodiagnosis and also to improve the ac- curacy of the process spreading detection up to 96%.
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 11 9. Complex and system registration of homeostasis parameters, oncopathology characteristics, interdependencies in the system “cancer-human organism”, anthropometric data based on the technology of expert systems allow to make reli- able qualitative-quantitative prognosis of postponed survival for every radically operated patient with malignancies of any localization and to estimate the life duration for non-radically operated concrete patient with the accuracy of up to 85%. 10. The developed methodologies of early, differential and corrected diagnosis, prognosis, immunodiagnosis and immu- nostaging of malignant neoplasm oriented for expert systems technology and computers make it possible to detect early and invasive oncopathology of any localization with high accuracy, to identify regional and distant metastasiz- ing, to estimate probable time of relapse and generalization of the process, to select patients for surgical, combined or complex treatment. It creates principally new opportunities for the optimization of the whole diagnosis-treatment process in terms of oncology and allows to reduce financial expenses and volume of instrumental check-ups by 2-3 orders in comparison with existing traditional programs. Ways of Introduction As a result of the research done in the present dissertation 5 new technologies of high-precision diagnosis and prognosiswere developed:1) “SUPERONCOSCREENING-1.0” System;2) “SUPERONCODIAGNOSIS-1.0” System;3) “SUPERONCODIAGNOSIS of METASTASIZING-1.0” System;4) “SUPERONCOPROGNOSIS-1.0” System;5) “SUPERONCOIMMUNOLOGY-1.0” System. The author developed 2 versions of every system. The first version is a full variant of the programs oriented on the tech-nology of expert systems and computers, ensuring the highest effectiveness, reliability and accuracy of oncopathology diag-nosis or prognosis. All the information on full versions of the systems is either patented or being patented by the patents ofRussian Federation. There are 15 patents:1) method of screening and differential diagnosis of malignant neoplasm;2) method of differential diagnosis of oncopathology and pre-cancer or non-malignant pathology;3) method of measuring the size of malignant neoplasm and total quantity of malignant cells in oncopatient’s organism based on the homeostasis parameters;4) method of diagnosis of distant metastases of oncopatients;5) method of diagnosis of generalization of oncopatients;6) method of diagnosis of early and invasive oncopathology for a single patient;7) method of diagnosis of malignant neoplasm metastasizing in regional lymphonoduses of a concrete patient;8) method of early and differential immunodiagnosis of malignancies;9) method of measuring the size of the malignancy and total quantity of malignant cells in the oncopatient’s organism based on the immunogram;10) method of immunodiagnosis of distant metastases of oncopatients;11) method of immunodiagnosis of generalization of oncopatients;12) method of immunodiagnosis of regional metastases of oncopatients;13) method of immunodiagnosis of early and invasive oncopathology for patients;14) method of prognosis of survival rate of radically operated oncopatients;15) method of prognosis of survival rate of non-radically operated oncopatients. The second version is maximally reduced and simplified for comprehension variant of the programs, specially adapted for ageneral practitioner of any level of medical care or for an oncologist, made in form of methodological recommendations forofficial use, allowing quite high service possibilities for early, differential and corrected oncodiagnosis, for prognosis of thesurvival rate of oncopatients and for immunodiagnosis of malignancies. This version is introduced in Omsk and Omsk re-gion. The list of the published author’s works on the theme of the dissertation1. Clinical Importance of Immunological Data of Patients with Gastric Cancer of Different Stages// Actual Questions of Oncology.-Kemerovo,1981.-N4.-P.200-201.2. Immunity Reaction to Post-Operational Trauma of Patients with Gastric Cancer of Different Stages// Extremal and Ter- minal States.-Alma-Ata,1981.-P.77-78.3. Diagnosis and Control over Gastric Cancer using Immunological Tests// Problems of Biology and Medicine.- Omsk,1981.-P.54-55.4. Immunological and Methabolical Parameters of Post-Operational Period of Patients with Gastric Cancer// Scientific- Technical Progress in Theoretical and Clinical Medicine.-Omsk,1981.-P.54-55.5. Immunological Data of Patients with Gastric Cancer in the Post-Operational Period// Questions of Oncology.-1983.-N4.- P.89-91.
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 126. Informativeness of Multi-Factor Correlation Modeling in Prognosis for Gastric Cancer// Using of Technical Aids in Diagnosis and Treatment of Gastric Cancer.-Omsk,1983.-P.50.7. Clinic-Morphologic and Immunologic Monitoring in Gastric Cancer Prognosis// Reports of Scientific Conference.- Omsk,1983.-P.98-99.8. System Analysis in Optimization of the Diagnosis-Treatment Process of Patients with Gastric Cancer// Actual Problems of Modern Oncology.-Barnaul,1985.-1,N1.-P.24-26.9. Computed Prognosis of Gastric Cancer for Every Patient// Actual Problems of Modern Oncology.-Barnaul,1985.-1,N1.- P.28-30.10. Criodestruction of Gastric Cancer as a Factor of Optimization of Treatment Process// Actual Problems of Modern On- cology.-Barnaul,1985.-2,N3.-P.193-194.11. Optimization of Surgical Treatment of Gastric Cancer using Cryogenic Method// Questions of Oncology.-1986,N2.- P.85-87.12. Optimization of Diagnosis-Treatment Process of Patients with Gastric Cancer as an Object of Automatization// Reports of Scientific Conference of Oncologists.-Omsk, 1986.-P.37-38.13. Mathematic Supply of Cybersystem for Optimization of Diagnosis-Treatment Process of Patients with Gastric Cancer// Reports of Scientific Conference of Oncologists.-Omsk, 1986.-P.32-33.14. Technical Supply for Cybersystem for Optimization of Diagnosis-Treatment Process of Patients with Gastric Cancer// Reports of Scientific Conference of Oncologists.-Omsk, 1986.-P.33-35.15. The System of Multi-factor Detection of Gastric Cancer in Optimal and Operational Diagnosis// Image Presentation of Data in Control and Scientific Research.-Moscow,1987.16. Adaptive Intellectual-Computed Prognosing in Optimization of the Treatment Process of Patients with Gastric Cancer// Actual Aspects of Prognosis Problem in Traumatology and Surgery.-Leningrad,1988.-P.70-72.17. Search for Optimal Solution in Diagnosis-Treatment Strategy for Patients with Gastric Cancer// Actual Problems of Modern Oncology.-Tomsk,1989.-N7.-P.159-168.18. Expert System in Oncology: Concepts, Problems, Prospects// Experimental Oncology.-1990.-12,N4.-P.9-16.19. Expert Systems in Oncology: Designing and Realization// Experimental Oncology.-Kiev,1990.-26pp.-Deposited in VI- NITI 16.07.90.-N4050-B90.20. Biometric Modeling in Optimization of Diagnosis-Treatment Process of Patients with Gastric Cancer// Clinical Surgery.- 1990.-N5.-P.9-10.21. Process of Making the Optimal Decision in the Diagnosis-Treatment Strategy for Patients with Gastric Cancer// Health Service in Turkmenistan.-1990.-N10.-P.33-37.22. Quick and Postponed Results of Combined Treatment of Patients with Gastric Cancer using Cryosurgery// Clinical Sur- gery.-1990.-N5.-P.19-20.23. Dynamic Synthesis of a Number of Gastric Cancer Developments in Optimization of Diagnosis-Treatment Process of a Single Patient// Health Services in Turkmenistan.-1990.-N10.-P.43-47.24. Optimization of Diagnosis-Treatment Process of Patients with Gastric Cancer as a Research Objective of the Theory of Planning and Analyzing of Multi-Factor Experiment// Int. Symposium Automated Information Systems in Oncology.- St.-Petersburg,1991.-P.67-69.25. Early Diagnosis of Gastric Cancer (Methodological Recommendations)// Omsk Medical Institute.-Omsk,1991.-6pp.26. Surgical and Combined Treatment of Gastric Cancer// Questions of Oncology.-1991.-N7-8.-P.788-795.27. Treatment of Patients with Gastric Cancer of the Forth Stage// Questions of Oncology.-1991.-N9.-P.907-916.28. Adjuvant Chemo- and Immunotherapy of Gastric Cancer// Experimental Oncology.-Kiev,1991.-24pp.-Deposited in VI- NITI 06.06.91.-N2383-B91.29. Logic-Linguistic Modeling in Optimization of Diagnosis-Treatment Process of Patients with Gastric Cancer// Int. Sym- posium Automated Information Systems in Oncology.-St.-Petersburg,1991.-P.69-70.30. Evaluation of Immune Homeostasis of Patients with Gastric Cancer// Experimental Oncology.-1992.-N3.-P.14-20.31. Postponed Monitoring in Prognosis of Gastric Cancer// Clinical Surgery.-1992.-N5.-P.4-6.32. Method of Differential and Early Diagnosis of Malignant Neoplasm (its Variants)// Application for a Patent from 27.04.92.-N5057959/040880.-28pp.33. Screening of Malignancies (Methodological Recommendations)// Omsk Medical Institute.-Omsk,1993.-7pp.34. Differential Diagnosis of Malignancies (Methodological Recommendations)// Omsk Medical Institute.-Omsk,1993.-5pp.35. Prognosis of Malignancies (Methodological Recommendations)// Omsk Medical Institute.-Omsk,1993.-6pp.36. Detection of Postponed Metastasizing and Generalization of Malignancies (Methodological Recommendations)// Omsk Medical Institute.-Omsk,1993.-5pp.37. Evaluation of Immune Homeostasis of Patients with Malignancies (Methodological Recommendations)// Omsk Medical Institute.-Omsk,1993.-4pp.38. Method of Prognosis of Life Duration of Oncopatients after Radical Operation// Application for a Patent from 10.02.94.- N4005926/005702.-27pp.
Kshivets O.M. Abstract of Dissertation for The Degree of The Doctor of Medical Sciences 1339. Method of Prognosis of Life Duration of Oncopatients with the Forth Stage of Malignancies after Diagnostic Surgeries// Application for a Patent from 14.03.94.-N94008771/008684.-12pp.40. Method of Differential Diagnosis of Malignant Neoplasm and Non-Malignant Pathologies// Application for a Patent from 08.11.94.-N94041043/040331.-18pp.41. New Organizational Methodological Approaches to Screening of Malignant Neoplasm// Int. Symposium New Organiza- tional Forms of Anticancer Struggle .-St.-Petersburg,1994.-P.13-14.42. System of Differential Diagnosis of Malignant Neoplasm// Int. Symposium New Organizational Forms of Anticancer Struggle .-St.-Petersburg,1994.-P.58-59.43. System for Survival Prognosis of Patients with Malignant Neoplasm// Int. Symposium New Organizational Forms of Anticancer Struggle .-St.-Petersburg,1994.-P.86-88.44. Expert System of Detection of Metastasizing of Malignant Neoplasm// Int. Symposium New Organizational Forms of Anticancer Struggle .-St.-Petersburg,1994.-P.57-58.45. System of Evaluation of Homeostasis of Patients with Malignant Neoplasm// Int. Symposium New Organizational Forms of Anticancer Struggle .-St.-Petersburg,1994.-P.55-56.