NeoMark is an EC-FP7-IST project investigating an innovative strategy and develops the appropriate technologies to identify person-specific and disease-specific biomarkers for tumours, to assess recurrence risk and early identify relapses during follow-up. The project validates this approach to Oral Squamous Cell Carcinoma (OSCC), which represents about 5% of all cancers, with a recurrence rate of about 25% to 50% over five years, 90% of which are within two years from surgery.

Knowing in advance which patients have a higher risk of disease reoccurrence would enable less invasive and earlier treatments, with the potential to improve patients' survival and quality of life.

A new approach to this problem requires the collection, aggregation and analysis of large sets of clinical data together with information on the biology of the disease and an advanced study of affected tissues by novel image-interpretation techniques to be applied on different diagnostic exams. NeoMark provides the powerful computational resources and accurate and refined analysis algorithms necessary to process this multi-dimensional and large amount of data, to find the characterising factors, or biomarkers, uniquely identifying the OSCC disease, like a personalised ID card (or bioprofile) of OSCC for each specific patient.  The NeoMark system will be able to detect the presence of such a bioprofile from the patient's data collected at follow-up, even when no signs of relapse are evident, so enabling early therapeutic actions.

The tools developed by NeoMark include advanced diagnostic images processing and feature extraction, which improve the evaluation of tumor and lymph-nodes characteristics such as size, volume, tissue and bone infiltration and water content and enable an objective quantitative measurement, at the same time providing valuable diagnostic and surgery support tools to oncologists and surgeons.

Neomark sets-up a collaborative environment for physicians and network of hospitals, where anonymous patient's' data are available for data analysis and disease bioprofile periodic update, taking into consideration more and more OSCC cases, so increasing knowledge on Oral Cancer and contributing to improve treatments and increase patients' life expectation, by early detecting markers related to disease onset.

For this scope, NeoMark intends to identify a reduced set of 'most relevant' genomic biomarkers characteristics of the disease and - in the final version - personalised for each individual patient, which could be assessed by means of a portable Real Time PCR 'lab-on-chip' device for a fast relapse risk evaluation, based on genomic data from blood or tissue RNA only. This innovative device would constitute, once approved through wide clinical trials, a powerful and low-cost diagnostic equipment.

The project started on 1 June 2008, is partially funded under the 7th Framework Programme by the European Commission, and will be completed in September 2011.

Policy Context

Early prediction of cancer reoccurrence constitutes a challenge for oncologists and surgeons. In the EU-Project NeoMark, scientists from different medical and biology research fields joined efforts with Information Technology experts to identify methods and algorithms able to early predict the reoccurrence risk for OSCC.

NeoMark starts from the need of researchers and clinicians in the field of oncology to improve the representation of biological processes related to the onset, growth, dissemination and relapse of human cancer. The project specifically addresses the challenge of the early prediction of relapses of Oral Squamous Cell Carcinoma (OSCC), a disease with considerable effects on patients due to its invasiveness in facial characteristics as well as speaking and eating abilities.

The main challenge is to design and develop algorithms able to identify a "signature'" or bio-profile of the disease, by integrating multiscale and multivariate data from medical images, genomic profile from tissue and circulating cells RNA and other medical parameters collected from patients before and after treatment. A limited number of relevant biomarkers will be identified and used in a real-time PCR device, for early detection of disease reoccurrence.

The idea behind NeoMark is that, by analyzing a sufficient set of different types of data (clinical, biomedical, genomic, histological, from digital imaging, from surgery evidence, etc.) of patients affected by OSCC before treatment and at the time of remission, a set of relevant biomarkers appearing only in presence of the disease might be identified. The recurrence of the same biomarker phenotype during post-remission follow-up may precede the clinical manifestation of the relapse thus allowing earlier intervention.

The main aim of the project is therefore the identification of a limited - but reliable - set of biomarkers (from clinical, imaging and genomic parameters) able to identify the re-appearance of the disease. The great quantities of data involved in this identification process - transcriptomic analysis alone involves tens of thousands variables - and the multi-scale dimension of bio-medical data to be considered, have so far prevented the integrated analysis of a patient's data.

NeoMark is therefore the first to attempt to solve this problem, and to do so a specific software will be developed to extract, integrate, process, relate, analyse, aggregate and present to clinicians different possible sets of related medical information (genetic, bio-molecular, imaging, clinical, physiology) in order to identify the most relevant factors associated with the disease and the risk of relapses, in search for a biological 'fingerprint' of the disease.

This 'fingerprint' will therefore constitute a touchstone for the individual patient's personal fingerprint, collected during patient's screening, pre-surgery visits and post-surgery follow-ups, to stage the probability of the disease, so contributing to early diagnosis and prediction of relapses.

NeoMark also sets up a collaborative environment for research on Oral Cancer, open to physicians worldwide interested in implementing the NeoMark protocol on their OSCC patients and so benefit from the early disease reoccurrence prediction tools at the same time contributing to the increase and accessibility of valuable clinical information useful to improve research and understanding of the miltiscale and multilevel factors related to Oral Cancer onset and evolution, and increase accuracy of the reoccurrence risk prediction algorithms.

Description of target users and groups

The users are physicians involved in OSCC diagnosis and treatment, operating in the fields of:

• Oncology
• Head & Neck surgery
• Dentistry and maxilla-facial surgery

Additional users are:

• Biomolecular researchers interested in the genomic aspects of Cancer
• Radiologists, in particular those specialised in Head & Neck imaging
• Pathologists who may be interested in the pathology-related factors relevant for Oral Cancer

Description of the way to implement the initiative

The NeoMark project will pursue the identification of 'bio-signatures' of the disease by implementing a software environment enabling collection, storage, and integration of heterogeneous biological data - coming from clinical, laboratory, histological, transcriptomic and imaging information - aiming at modelling progression/ recurrence of regionally limited Oral Squamous Cell Carcinoma with two major purposes:

1. to identify subjects at higher risk of cancer reoccurrence after reaching remission;
2. to detect early the presence of loco-regional recurrence undergoing traditional surgical plus medical treatment.

The identification of a limited number of biomarkers, specific for the individual patient's profile of the disease, will be translated into a 'lab-on-chip' test device for early identification of potential risk of relapse.

The NeoMark clinical study and research will test the accuracy of this device on the enrolled patients, so providing data for a possible approval of this device by the European Authorities and by FDA. This ambitious goal may also lead us to the identification and development of an innovative, low-cost, portable, diagnostic device, usable by dentists and by physicians for OSCC screening purposes, so implementing the disease-prevention strategies of European health systems.

The NeoMark vision implies the identification of specific scientific objectives as well as technical objectives.

 The technologies developed in NeoMark will lead to the realisation of two functional environments: one for the definition of biomarker profiles and one for the follow-up of the evolution of the disease. They will be based on the 'fusion' of information from clinical data from:

• health records and standard laboratory markers;
• histological data from tumour mass specimens;
• high-throughput genomic data from tumour tissue specimens and circulating mononuclear cells, profiling gene expression at whole genome level by oligo-RNA microarrays;
• imaging data of the prime tumour mass (and secondary localisations if present) through imaging techniques, including image fusion, where relevant.

This vision pursued by NeoMark is based on the development of innovative algorithms for the analysis of different categories of data (genomic, imaging, histology, biological, clinical), advance data organisation and data mining techniques, refined statistical tools, user-friendly and accurate user presentation methodologies, and user interfaces based on interoperable platforms.

A portable medical device to analyse this 'fingerprint' will also be produced at the end of the project, to facilitate and anticipate the prediction or detection of OSCC during screening of at-risk population and after treatment, during follow-ups.

The analysis of the heterogeneous data constitutes the cornerstone of the NeoMark artificial intelligence. This tool to assesses the risk of reoccurrence in the very early stages of treatment, i.e. as soon as the patient reaches remission, and efficiently and effectively models the disease evolution during the whole follow-up period based on a multitude of heterogeneous data, thus predicting the disease evolution. Using this tools physicians can stratify patients by reoccurrence risk probability at the time of diagnosis and use this information to decide the most appropriate treatment, and to monitor reoccurrence probability during patient's follow-up, so orienting the post-treatment therapeutic approach.

In NeoMark the progress of the disease in a total of almost 150 patients with oral squamous cell carcinoma is evaluated. Due to the complex nature of cancer, a collective approach must be considered which involves the integration and analysis of multiscale data. Specifically clinical, imaging and genomic data are assembled ranging in the scale of dimension and localisation. Moreover, a personalised genetic signature aims to capture patient-specific perturbations of the disease evolution in its molecular basis. For each patient the gene expression values before treatment (cancerous profile) and in the first stages of remission (cancer-free profile) are compared. The outcome is a set of differentially expressed genes representative for each patient, which constitute a personalised genetic signature. The expression of these genes from all follow-up visits is compared in turn with the cancerous and the cancer-free profile, calculating the correlation and the Euclidean distance; these metrics provide, respectively, a qualitative and quantitative measure of the patient's prognosis.

Technology solution

The versatile user requirements and especially the integration of heterogeneous input data required a careful design of the NeoMark system. Our goal was to integrate as much functionality as possible in a single unified service oriented system, achieving great flexibility and usability. These properties increase the user acceptance and may decrease human error. The proposed architecture is a service-oriented architecture (SOA) able to support the use of Web services to ensure interoperability between different systems. There are some individual applications that work as modules in the system in order to provide a single starting point to meet the needs of the users that can add new information, review and edit available data and make analyses with the stored information. The main module of this architecture is the data repository located on the NeoMark Server. For the interaction with this central component there are some different tools for Data Entry, Genomic Analyses, Imaging processing, Data Mining and Security. Some of those tools have a web-based access point and the others for some computational constraints are located on the client's machine, but always with an interaction with the central unit. The NeoMark System is scalable because we can easily add in new hospitals or centres that after a small initialisation procedure (Sensitive Data database and standalone application) can immediately start with the data storage and with the data analyses. The central repository stores all the collected heterogeneous data coming from the different modules and layers of the system, duly anonymised to ensure privacy. Sensitive patient's data, used by physicians to deliver therapy, are stored in separate local databases in each specific hospital's network in order to be accessible only by local authorised doctors.

The NeoMark Integrated platform integrates all the different components in charge of data collection and data analysis and provides data representation and reporting functionalities used by physicians to monitor patient's status and to take decisions on treatments and therapies.

Most of the user interaction is done via the web interface. The physician can manage patients, enter clinical data, view all features and the NeoMark results. The clinician can upload genomic data and researchers can view anonymous statistics, which could serve as a base for future research on oral cancer. However there are three exceptions to this architecture:

• The NeoMark Electronic Health Records management tool is the data collection tool, specifically designed for the collection, storage and management of all etherogeneous and multiscale data used in NeoMark. The tool collects data manually inserted by the authorised physicians and researchers, uploaded from the Image Processing Tool and from the Genomic Data Cleaning and Filtering Tool and presents data aggregations and reoccurrence risk prediction and disease evolution trends in paper and on screen.
• The NeoMark Image Processing Tool. This standalone Win64 application is installed on the radiologist's workstation. It is used to semi-automatically extract relevant features from medical images. Due to the huge amount of imaging data and the computational complexity of the sophisticated image processing and analysis algorithms, it was not feasible to integrate this functionality in the rest of the system. However the tool is connected to the NeoMark system via a network connection. The task of the feature extraction module is to extract from that huge amount of data meaningful numeric features from tumours and suspicious lymph nodes that appear to be important for reoccurrence prediction.
• The Genomic Data Cleaning and Filtering is used to analyse information taken from gene expression data coming from Feature Extraction (FE) files. The analyses in based on Control and Duplicate Features, Filtering of Genes based on low data quality and Filtering of Genes with high number of missing values taken from. The relevant information that is stored in the database is Feature Name, Probe Name Gene Name, Systematic Name, Description and Log2-ratio. Application generates as output a cleaned file with a small dimension that contains only this relevant information and that can be uploaded from a specific page of NeoMark WebApplication into the database.
• The Data Analysis and risk Prediction tool. The proposed prognostic model is based on DBNs, which are temporal extensions of Bayesian Networks (BNs). A snapshot of the patient's medical condition is acquired during every predefined follow-up by the doctor. By exploiting the information of history snapshots we aim to model the progression of the disease in the future. In the first step we filter the initial pool of genes by removing duplicate and control genes, as well as genes with high percentage of missing values.
• The PCR Chip Upload Tool. This tool downloads genomic features from a PCR chip reader device and submits them to the NeoMark system. Due to the direct access to external hardware, this tool could not be integrated, but rather is a standalone application which is installed on the clinician's workstation. The qRT-PCR platform is under development in STMicroelectronics, in order to obtain quantitative information about the PCR amplification of the targeted genes. It is a portable, real-time, integrated analytical system based on qRT-PCR performed in an array of silicon micro chambers. The small size of the components, as well as its low power requirements make this system an ideal candidate for further miniaturisation into a hand-held, point-of-care device. The qRT-PCR lab-on-chip is disposable and relatively inexpensive in order to make this method of analysis economically viable. The excellent thermal conductivity of silicon makes it ideal in applications requiring rapid cycles of heating and cooling.

Technology choice: Standards-based technology

Main results, benefits and impacts

Expected Results

Scientific results

NeoMark research is oriented to find a tool and to experience a methodology for assisting physicians in a more effective care of a particular family of cancer, whose numbers are increasing, and which have not been extensively studied and investigated so far.

Therefore, the main contributions that NeoMark expects to bring to research is a better understanding of the correlations between biological factors (personal for each patient and specific for the addressed cancer, Oral Squamous Cell Cancer) that are characteristic of oral cancer and fostering reoccurrences.

The emphasis placed by NeoMark partners on the evaluation and processing of integrated data from each patient and from many patients with similar cancer is expected to lead us to the identification of some prominent markers which, tested on a sample of patients, will be experimentally analysed on a prototype medical diagnostic device based on RNA micro-array techniques and on chip-based RT-PCR technologies.

Therefore the NeoMark follow-up methodology followed in the project, the NeoMark data acquisition and analysis system, including advanced image feature extraction and analysis and interpretation tools, and the NeoMark lab-on-chip diagnostic device, are expected to bring significant contributions to clinical knowledge, to early diagnosis of oral cancer relapses and to the simplification of the diagnostic procedures.

Additionally NeoMark expects to provide a proof of concept that ICT may help in building models of patterns of behaviours of disease evolution for Oral Squamous Cell Cancer, so as to encourage the adoption and further improvement of NeoMark tools in wide clinical trials. As for the achievements at the end of Neomark research, the consortium will work to achieve a system for helping clinicians in their decisions for treatments and intervention methodologies, based on the availability of aggregated and complete data, showing trends of oral cancer in relation to specific biomarkers and imaging aspects, currently not possible due to the lack of integration and to the enormous number of genetic data to be processed.

Technical results

NeoMark technical development will bring up new technologies in the area of integromics, data analysis algorithms and diagnostic image processing and interpretation.

The developed innovative technologies include:

• Diagnostic images management and feature extraction (developed by Fraunhofer IGD- Darmstadt, Germany);
• RT-PCR Lab-on-chip for RNA analysis and relevant software (developed by STMicroelectronics, Italy);
• NeoMark Oral cancer Ontology (developed by Universidad Politecnica De Madrid, Spain);
• NeoMark OSCC reoccurrence risk prediction tool and algorithms (developed by University of Ioannina, Greece);
• NeoMark Integrated Platform (developed by Multimed Srl, Italy and Link Consulting, Portugal).

These results will be substantiated into software tools - integrated into the NeoMark platform - and medical devices for diagnostic purposes. Such technologies promise to open new approaches for cancer relapse risk screening, with wide market potential.

Return on investment

Return on investment: Not applicable / Not available

Track record of sharing

The project was extremely complex from the medical side, because of its innovative scientific and research approach which required the recruitment of patients during the project duration and involved many different clinical researchers operating in different fields and hospital departments.

The experience of NeoMark was shared within the VPH NoE initiative and among the scientific and medical environment at European and International level.

NeoMark is so far the first research in the field of Oral Cancer managing such a variety of data and involving such a numerous patients' cohort. As such we expect that the results of the project have effective impact on the approach to Oral Cancer treatment and patients management.

Lessons learnt

The project was extremely interesting and challenging and difficult to manage for the many technical and clinical aspects involved. We have identified the following critical aspects to be carefully addressed:

1. Multicenter clinical studies must be carefully planned and organisational aspects solved before the start of the study, in order to minimise delays and increase efficiency.
2. Involvement of users (in our cases physicians) is key to optimise the technical development and to obtain positive assessment of the developed tools. The strict collaboration between users and technical developer established in NeoMark from the very beginning strengthened the Consortium and increased productivity and quality of work.
3. The development of IT solutions which will be operated in hospitals requires an early and careful analysis involving the hospital IT departments managers, in order to correctly approach the integration inside the existing hospital IT infrastructure and to adapt to the established standards, policies and practices. This aspect was a key point in the early stages of NeoMark and was key for our development.

Scope: International