Childhood Visualized Cancer-Registry
Development and Demonstration of the Methodology and Information Technology for Making the Diagnosis of Childhood Cancer on the Basis of the Visualized Findings of the Primary Diagnostic Complex
Tech Area / Field
- INF-SOF/Software/Information and Communications
8 Project completed
Senior Project Manager
Isakov S V
National Academy of Sciences of the Republic of Belarus / Institute of Informatics Problems, Belarus, Minsk
- Belarusian Research Center for Pediatric Oncology and Hematology, Belarus, Minsk
- Universita degli Studi di Salerno / Dipartimento di Ingegneria dell'Informazione ed Ingegneria Elettrica, Italy, Salerno\nUniversity Hospital of Lille / Department of Nuclear Medicine and Functional Imaging, France, Lille\nMedizinische Hochschule Hannover, Germany, Hannover\nFrench National Registry of Children Solid Tumors, France, Vandœuvre lés Nancy
Project summaryThe project's purpose is the development of a new approach and information technology (IT) for the diagnosis of childhood cancer diseases, supposing a comprehensive evaluation of the set of the tumor cell features, employing the visualized findings of the primary diagnostic complex.
The state of the art in the field of the diagnosis of childhood cancer diseases. A comparatively low level of childhood malignant neoplasm incidence in the pattern of overall cancer incidence in the population necessitates complete registration of childhood cancer cases and their detailed analysis. It is needed for detection of possible etiologic factors of the disease, determination of the distinctions in the course of the tumor disease in different age groups of children, investigation of the morphofunctional properties of tumor cells for various nosologic forms of childhood cancer.
Making a diagnosis of malignant tumours occurred at children's age is a multistage procedure. Both specificities of a macroorganism (of a child in this case: age, residence, associated diseases, etc.) and tumoural cells (cytological, cytochemical, cytogenetic, molecular-genetic, immunohistochemical, morphological characteristics) and interaction of a macroorganism and a tumour are taken into account. It is reflected in the extension of tumoural process and its prognostic signs. Children’s survival rate has been considerably improved by the application of modern protocols of children's cancer treatment. However there is unresolved till now the problem of primary resistance of tumoural cells in some cases and the problem of disease relapse. The reason of failure to respond to malignant tumor therapy lies in the interpretation of making elements of the primariest diagnostic complex which besides general group characteristics of tumoural process contains inpidual characteristics of the interaction of a macroorganism and tumoural cells, as well as in subsequent response to induction therapy.
Modern methods of diagnostics and monitoring of tumoural process have complex character and make necessary the participation of various experts (clinicians, doctors-laboratory assistants, radiologists, doctors of functional diagnostics, immunologists, cytologists, morphologists, geneticists, biologists). Complexing of all available findings (data) and composing of the uniform and developed representation of disease are an important step in multistage diagnostics.
In making the diagnosis of malignant neoplasm in childhood, the visualized findings (microscopic images, X-ray roentgenograms, tomograms and sonograms) make up more than 90% of information. The project supposes development of a new IT of their full registration using so-called visualized complexes (cards), computer-aided processing and support of decision-making in children's oncology that will allow to optimize and speed up the diagnostic process.
The international criteria for making a confident diagnosis (C-factor or certainty factor) applied at present in compliance with WHO recommendations provide for the following levels of diagnosis: C1 standard clinical examination of a patient; C2 clinical and instrumental research methods, cytological research; C3 tumour biopsy, morphological research; C4 histologic examination of a section material; C5 evidence from autopsy TNM Atlas / pTNM Classification of Malignant Tumours. Ed. by B. Spiessl, et al. 1997. The last two criteria provide little information in childhood oncology since chemoradiotherapy changes both the biological properties of the tumor cell and the extent of tumor spread in the child's body. In this connection, the primary diagnostic complex - a collection of the features which define the morphofunctional nature of the tumor disease and its spread in the given patient, for making the diagnosis of childhood cancer and the degree of its confidence are vital for treatment stratification and have a direct effect on the patients survival.
This project is intended to develop a new methodological approach for the estimation of the primary diagnostic complex criteria of various nosologic forms of malignant neoplasms in childhood, based on the comprehensive analysis of the macroorganism and morphofunctional properties of tumor cells as a whole, using the visualized diagnostic findings. Investigation of the primary diagnostic complex at children with oncological and hematological diseases (leukaemia, lymphoma) and CNS tumours is supposed to be done. These groups of diseases make more than 60% of all oncopathology at children's age in the Republic of Belarus (the RB).
To demonstrate the vitality of the approach for comprehensive evaluation of the combination of the properties of tumor cells for making a diagnosis, a registry pilot prototype of the visualized findings of the primary diagnostic complex for children’s malignant tumours in the Republic of Belarus will be established based on the developed IT for collection, processing and analysis of the images and data. Evident record-keeping of clinicobiological properties would make it possible to detect the distinctive features of the tumor disease with regard to its territorial distribution. According to research results obtained by Belarusian Research Center for Pediatric Oncology and Hematology (BRCPOH) specialists there is a prevalence of pre B immunophenotype in children with acute lymphocytic leukaemia (ALL) that considerably differs from ALL structure in other countries. As a result of studies there has been revealed in Belarusian children an increased ALL rate with coexpression of myelomarkers. There has been reported a high rate of Т-linear antigene CD2 coexpression on В-linear ALL cells in children in the RB which has made 36,3% and exceeds world data in 10 times. There have been gathered data on a high morbidity rate of lymphogranulomatosis in children, this level is the highest among the European countries. Thus the received data point to existing distinctions of clinical and diagnostic manifestations of some oncological diseases in children of the RB.
Scientific novelty of the project consists in the development of a visualized and objectively integrated in medical - diagnostic process primary diagnostic complex for some nosologic forms of children’s cancer that will allow to make a comparison of diagnostic signs of the same oncopathology in children of Belarus with those in other (European) countries. There will be conducted a multiple factor analysis of identifying parameters of the visualized primary diagnostic complex (macrodiagnostic parameters, immunologic and genetic characteristic of tumoural process) in groups of different sex and age. The project scientific value is specified by the fact that there will be made a comparative analysis of the primary diagnostic complex data in children with malignant tumours living in various regions of the RB, including territories with radionuclide contamination after Chernobyl disaster.
The impact of the proposed project on the progress in the field of childhood oncology. The expected results of the project implementation are important from the point of view of extending international scientific cooperation in the field of childhood oncology, and the reasons for that are as follows:
- in the introduction of the unified estimation approaches to the extent of tumor spread and follow-up monitoring of the patients, a multiple factor analysis made on population groups will be provided. The purpose of the analysis is to study macroscopical tumour features with the use of visualization methods and morphofunctional characteristics of tumoural cells depending on the place of residence of a patient in order to reveal potential risk factors and to make a prognosis for children's cancer;
- further dynamic analysis of primary - resistant forms of children's cancer is possible while giving a special treatment;
- database is formed within the uniform co-operated study protocol for the analysis of long term effects of chemoradiotherapy in children.
Competence of the project team. The scientists and specialists in the IT field from IEC NASB (Leading Institution) and also in the medicine field from BRCPOH (Other Participating Institution) will be involved in the fulfillment of the project tasks. The employees of IEC NASB have significant scientific experience in the field of processing and recognition of medical images, they have created computer hard- and software complexes for collection and processing of ultrasound, X-ray and radioisotope medical images and computerized control systems for medical centres on the basis of the electronic case history in more than 30 medical institutions of Belarus. For the time being the database of these medical institutions comprises comprehensive information about more than 50, 000 patients, including more than 1 000, 000 diagnostic images. The leading specialists of BRCPOH have gained wide experience in evaluation of the primary diagnostic complex for childhood malignant neoplasm. Besides the classical methods of cytological and histologic examination of tumor cells and tissues, they apply immunophenotyping and immunohistochemistry techniques which makes it possible to supplement the morphofunctional characteristic of the tumor and to precisely define the nosologic form of the disease, to specify the prognostic groups of the disease and subsequently stratify the treatment. Since 1994 BRCPOH employees have widely used cytogenetic studies and cell cycle analysis in clinical practice to detect chromosomal aberrations and hyperploidy of tumor cells. Since 1997 polymerase chain reaction (PCR) methods of molecular and genetic analysis of tumor cells have been employed to detect chimeric oncogenes. Owing to up-to-date diagnostic equipment available in BRCPOH, the estimation of the extent of tumor spread in children has become much more reliable. In BRCPOH the Childhood Cancer Sub-register was established, in which all the cases of childhood malignant neoplasms in the Republic of Belarus have been registered since 1989. At present the database of the childhood cancer sub-registry includes more than 5500 cases, the clinical and morphological examinations of all the cases being conducted. The Childhood Cancer Sub-register data are used in the ACCIS (Automated Childhood Cancer Information System) international project under the aegis of the IARC (International Agency for Research on Cancer, Lyon).
In BRCPOH about 90% of the children with oncohematologic pathology and CNS tumours in the RB receive specialized treatment. Thus, there is a real opportunity to create a visualized register of primary diagnostic complex with a high degree of data representativeness on the population level.
Expected results. The next results are expected to be achieved on the accomplishment of project tasks:
- advanced specified on childhood cancer diagnostics algorithms and software for processing and recognition of images of biological objects;
- an approach, reliability criteria and IT for making a confident diagnosis for various nosologic forms of childhood cancer based on the comprehensive evaluation of tumour process images;
- techniques, algorithms and software for creation of electronic atlases of biological objects images and making their comparative analysis for differential diagnostics of oncohematologic diseases and CNS tumours in children;
- a multiple factor analysis method for visualized characteristics of biological objects at oncohematologic diseases and CNS tumours;
- a pilot prototype of the visualized findings register of the primary diagnostic complex in Belarusian children with malignant tumours.
Application of expected results. Implementation of the project results will form the basis for:
1) development and patenting of the commercial products as the library archives of the visualized findings of the primary diagnostic complex for malignant neoplasms in children that can be applied in various international projects in the field of childhood oncology and oncohematology, in training of medical students and doctors;
2) establishment of the uniform information and diagnosis environment of Belarusian medical institutions providing specialized care for children with malignant neoplasms, for the purpose of improving the quality of medical diagnostic service and efficient decision making.
Execution of the project will allow to fulfil the following goals and objectives of ISTC:
- to offer Belarusian weapon-oriented scientists and specialists participating of the project, before connected with the development of biological weapon and rocket technologies of its delivery and also methods for armament and military equipment protection from high-precision radio controlled weapons - an opportunity to redirect their skills to peaceful activities in the field of a childhood oncology;
- to support applied research and new integrated IT development for making a diagnosis of childhood cancer for solving a topical scientific and practical problem in the field of childhood health;
- to reinforce transition to market-based economy responsive to civil needs in the field of human health protection by way of designing tools for development and patenting of the commercial products as the electronic atlases of the malignant neoplasm images.
Scope of activities. The purpose of the project will be attained within 36 months as a result of the fulfillment of the following four tasks:
1) developing the information model, the choice of methods for tumour process study and creating hard-and-software tools to form visualized findings of the primary diagnostic complex (estimated effort - 180 man*months);
2) developing a comprehensive approach for estimation of the clinicobiological features of the tumor process for making a diagnosis of oncohematologic diseases and CNS tumours in children (estimated effort - 104 man*months);
3) creating a methodology and software for differential diagnostics of oncohematologic diseases and CNS tumours in children based on visualized complexes (estimated effort - 105 man*months);
4) creating a register pilot prototype of the visualized findings of the primary diagnostic complex at malignant tumours in children (estimated effort - 99 man*months).
All tasks include research of childhood cancer diagnostics (BRCPOH) on the one hand and of processing and recognition of pathological affection images (IEC NASB) on other hand. At investigation stage there will be created an archive of not less than 400 primary visualized complex charts of patients with leukaemia, lymphoma, CNS tumour. The software will consist of about ten packages including about 80 basic and 150 service functions.
Role of foreign collaborators. In the course of the project implementation, Department of Pediatric Hematology/Oncology, Hanover Medical School (Germany) will be involved in the solution of the problems related to technique development and research work on multiple factor analysis of visualized characteristics of biological objects at oncohematologic diseases and CNS tumours. Dipartimento di Ingegneria dell'Informazione ed Ingegneria Elettrica, Universitа degli Studi di Salerno (Fisciano, Italy) will be involved in carrying out the project's scientific and technical tasks on development of advanced, aimed to childhood cancer diagnostics, algorithms and software for processing and recognition of biological objects images. Department of Nuclear Medicine and Functional Imaging, University Hospital of Lille (France) will be involved in carrying out the project's scientific and technical tasks on development of visualization methods of various images on one monitor in a "merging" mode for the simultaneous analysis, integrated processing and estimation of the findings received during several examinations for the subsequent definition of tumour process prevalence.
During project execution the scope of cooperation with the foreign collaborators:
- information exchange and joint workshops in order to discuss the course of project implementation and estimate scientific and technical level of the obtained results;
- participation in clinical tests by using developed instrumental methods and created hardware-software tools;
- provide comments to the technical reports, submitted by project participants to the ISTC.
Technical approach and methodology. Task 1 is to result in the development of information model for complex diagnostics of oncohematologic diseases in children (acute lymphoblastic leukaemia, acute myeloblastic leukaemia, myelodysplastic syndrome, Hodgkin’s disease, non-Hodgkin’s lymphoma) and CNS tumours (ependymoma, astrocytoma, embryonic CNS tumours, mixed glioma, craniopharyngioma) and of a coding data system. Algorithms of digitizing and pre-processing of the images obtained from diagnostic equipment as well as invariant hardware-software tools of registering and a prototype of visualized database of the primary diagnostic complex will be developed. During investigations, it is supposed to register the following visualized parameters of the primary diagnostic complex in an electronic card: 1) clinical and instrumental methods of examination (ultrasonic, roentgenography, computer tomography, magnetic resonance tomography); 2) cytological methods, immunologic, cytogenetic and molecular genetic research methods of tumour cells; 3) morphological research methods (including immunohistochemical study).
Task 2 is to lead to a new method, reliability criteria and IT of making the diagnosis of various nosologic forms of childhood cancer based on a comprehensive evaluation of tumour process images. An integrated IT including invariant functions of automatic and interactive segmentation and vectorization of images of biological objects, optimized for oncohematologic diseases and CNS tumours in children, will provide automatic or computer-aided diagnostics of malignant disease by processing the database of certain morphometric and textural parameters of microscopic images of tumour cells. At the topological evaluation of X-ray roentgenogram, tomogram and sonogram, functions of the calculation of contour, linear and angular features will be used for determining descriptors of objects in the image. For the identification of nosologic forms of childhood cancer there will be developed methods of allocation of inpidual objects and groups of objects having the same attribute, for example, colour, form, structure, etc. It is supposed a visualization of various images on one monitor in a "merging" mode for the simultaneous analysis of images of various diagnostic types and their joint processing and also integrated processing of the data received during several studies. The information will be recorded in the database for the subsequent definition of tumour process prevalence and the diagnosis of cancer in children. An original methodological approach to the creating of visualized findings of the primary diagnostic complex will allow to standardize clinical and morphological research criteria while accomplishing Task 2.
Within Task 3 in order to make differential diagnostics of various nosologic forms of oncohematologic diseases and CNS tumours in children there will be created an electronic atlas of images (microscopic images, X-ray roentgenograms, tomograms and sonograms) of main forms of biological objects’ diseases, quantitatively and qualitatively systemized and giving the picture of pathological changes. There will be developed algorithms, software and techniques of automated comparative analysis of digital images - a sample under study and reference images of the electronic atlas. A supposed automatic analysis of images with recognition elements will allow to speed up considerably the choice of the necessary form of cancer disease. Having evaluated 20-50 fields of the examined image and on the basis of a set of answers the software will have to verify automatically the diagnosis. The software supporting the electronic atlas will be provided with functions of work with the image library, improvement of reference and analyzed image quality, automatic allocation of objects and decision-making. Within Task 3 the developed technique will become the basis of multiple factor analysis of biological object images at oncohematologic diseases and CNS tumours in children in various sex and age groups with distribution on regions, including territories with radionuclide contamination after Chernobyl’s disaster.
The developed information technologies for an uniform visualized complex of the primary diagnostic findings in children with malignant tumours need specialized software development for supporting remote users on a national scale and for data exchange with foreign medical centres via Internet (Task 4).
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