Perspectiveson Digital Pathology 3M. García-Rojo et al. (Eds.)lOSPress, 2012

© 2012 The authors and IOS Press. AU rights reserved.doi:10.3233/978-1-61499-086-4-3

The COST Action IC0604 "TelepathologyNetwork in Europe" (EURO-TELEPATH)

Marcial GARCÍA-ROJO Luís GONCALVES " andBemd BLOBEL'^Hospital General Universitariode Ciudad Real, CiudadReal, Spain. COSTAction

IC0604 Chair

Administragáo Regional de Saúde doAlentejo, LP. Portugal COST Action IC0604Vice-Chair

""eHealth Competence Center, University Hospital Regensburg, Regensburg, Germany.COST Action IC0604 WG 2&4 Co-Chair

Abstract. The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH) is a European COST Action that has been Rinning from 2007 to2011. COST Actions are ftinded by the COST (European Cooperation in the fieldof Scientific and Technical Research) Agency, supported by the SeventhFramework Programme for Research and Technological Development (FP7), ofthe European Unión. EURO-TELEPATH's main objectives were evaluating andvalidating the common technological framework and communication standardsrequired to access, transmit and manage digital medical records by pathologistsand other medical professionals in a networked environment. The project wasorganized in four working groups. Working Group 1 "Business modelíng inpathology" has designed main pathology processes - Frozen Study, FonnalinFixed Specimen Study, Telepathology, Cytology, and Autopsy -using BusinessProcess Modeling Notation (BPMN). Working Group 2 "Informatics standardsin pathology" has been dedicated to promoting the development and applicationof informatics standards in pathology, collaborating with Tntegrating theHealthcare Enterprise (IHE), Digital Imaging and Communications in Medicine(DICOM), Health Level Seven (HL7), and other standardization bodies. WorkingGroup 3 "Images: Analysis, Processing, Retrieval and Management" workedon the use of virtual or digital slides that are fostering the use of image processingand analysis in pathology not only for researchpurposes, but also in dailypractice.Working Group 4 "Technology and Automation in Pathology" was focusedonstudying the adequacy of current existing technical solutions, including, e.g., thequality of images obtainedby slide scanners, or the efficiencyof image analysisapplications. Major outcomeof this action are the collaboration with intemationalhealth informatics standardization bodies to foster the development of standardsfor digital pathology, offering a new approach for workflow analysis, based inbusiness process modeling. Health terminology standardization research hasbecome a topic of high interest. Future research work should focus onstandardization of automatic image analysis and tissue microarrays imaging.

Keywords. Digital pathology, digital slide, business modeling, DICOM, HL7, IHE,SNOMED CT, image analysis, slide scanner.

1 Corresponding Author. Marcial García Rojo, MD, PhD; Dep. of Pathology, Hospital GeneralUniversitario de Ciudad Real, Calle Obispo Rafael Torija s/n, E-13005 Ciudad Real, Spain; Email:marcial@cim.es: Phone: +34-926-278166; Fax: +34-926-278186; URL: http://www.conganat.org/eurotelepath/

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Introduction

EURO-TELEPATH stands for "Telepathology Network in Europe", a European COSTAction IC0604 (http://www.conganat.org/eurotelepath/) that has started in 2007 andended in November 2011. This COST Action aimed at fostering collaboration betweenEuropean research groups working on an adequate technological framework for themanagement of multimedia electronic healthcare records covering both data andimages, but also on standards and applications for processing such multimediainformation in anatomic pathology and communicating it with the clinical domain. Thestandardization work is performed in cióse collaboration with related intemationalstandards developing organizations (SDOs) [1].

COST (European Cooperation in Science and Technology) is a Europeaninstrument supporting cooperation among scientists and researchers across Europe,supported by the European Unión Research and Technological Development (EURTD) Framework Programme. COST Action IC0604 belongs to the domainInformation and Communication Technologies (ICT), focusing on methods andtechnologies for managing multimedia electronic healthcare records, ICT applied toanatomic pathology, research on standards for digital medical images, worldwidesearch engines, and collaboration with standardization bodies.

The main objective of COST Action IC0604 (EURO-TELEPATH) wasconsolidating the most renowned research references in the field of informatics appliedto anatomic pathology in order to develop, with support of national and other Europeanprograms, the fusión standards to represent, interpret, browse and retrieve digitalmedical images while preserving their diagnostic quality as needed for clinical,leaming and research purposes.

This coordinated research was able to open the path to search, access, exchange,integration, and upgrade of digital pathological images and associated reports amongdifferent hospital information systems regardless of their location. Based on commonstandards developed by the European Committee for Standardization (CEN), the WorldWide Web Consortium (W3C) and other Standards Developing Organizations (SDOs)such as DICOM, HL7, or SNOMED, the direct result of this COST Action wascollaborating in the elaboration of new Pathology Technical Frameworks (IHEPathology) to be taken as a new reference standard by the specialized E-health industryas well as the entire medical community.

1. Project Mission, Scope and Structure

1.1. Digital Pathology

The concept digital pathology includes the use of múltiple digital images (gross studies,microscopic, and molecular pathology images), including whole slide microscopicdigital images, integrated with pathology information systems, enterprise imagerepositories, and electronic health record. The main challenges in digital pathology areeducational, technological, and the complexity of health information systems.

EURO-TELEPATH's main objectives are evaluating and validating the commontechnological framework and communication standards required to access, transmit andmanage digital medical records by pathologists and other medical professionals in anetworked environment.

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Research directions in EURO-TELEPATH are focused on:

• Automation procedures in pathology. Best technology available and underresearch.

• Scanning solutions for pathology microscopic sHdes.• Technological solutions for compression and storage problems with large

image files.• Virtual slide standard viewer specifications which allow efficient reviewing of

pathology images.• Intemational standards such as Digital Imaging and Communications in

Medicine (DICOM), Health Level Seven (HL7), and SystematizedNomenclature of Medicine-Clinical Terms (SNOMED CT), EuropeanCommittee for Standardization (CEN) and Integrating the HealthcareEnterprise (IHE) initiative.

• Models for pathology and other hospital information systems.• An European-scope telepathology network.• Collection of interesting and typical samples, and clinicopathological sessions.

Three main areas of research have been developed:• Research in general business process in pathology to help in the best use of

existing standards (DICOM,HL7,jpeg, web services, reference terminologies,etc.) to implement the business processes for both patient care and research inAnatomic Pathology. These standardization efforts conducted within IHE(Integrating the Healthcare Enterprises) [1] influenced the work of DICOM,HL7 and the JPEG community. The current IHE Anatomical PathologyTechnical Framework ready for implementation and new Integration Profilesare defmed every year [2].

• Images Analysis and Processing in Pathology has become an essential elementof the modem diagnostic pathology. During this session physicians, biologists,and IT specialists can leam about emerging standards and the tools of digitalpathology improving immunohistochemical evaluation of digital slides. It willbe an opportunity to enter into a dialogue with the intemational expertsinvolved in new trends of digital pathology.

• Automation in Digital Pathology research is aimed to analyze the integrationof new automated instruments in pathology, including immunohistochemistrysolutions. New research in microscopic digital imaging (virtual slide solutions,slide scanners) needs to be considered [3].

Sixteen countries have participated in EURO-TELEPATH. In order to achieve theaforementioned objectives, research work was structured in four working groups.Working Group (WG) 1 is called "Pathology Business Modeling" and has beenworking in a consensus study of existing workflows in pathology departments. WG 2"Informatics Standards in Pathology" mainly dealt with the active participation inrelated standards bodies and initiatives. WG 3 'Images: Analysis, Processing, Retrievaland Management" has been elaborating studies on image analysis models in pathology(methods, systems, tools), and WG 4 'Technology and Automation in Pathology" wasworking on the analysis of microscope brands and scanning solutions [4].

In this paper, we will describe the main work performed by all working groupsrelated to IT standards in digital pathology.

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1.2. Inter-Disciplinary Networking

COST Action IC0604 is an interdisciplinary consortium (mainly medical doctors,electrical engineers, and software engineers). Along with anatomic pathology, othermedical research areas, like radiology imaging, can also benefit from Action work [5].

COST Action IC0604 has organized a workshop at the Medical InformaticsEurope 2009 (MIE) Conference, held fi-om 30 August through 2 September 2009 inSarajevo, Bosnia & Herzegovina. Further COST Action IC0604 activities werepresented at the 24th Meeting on Software and Database Engineering held in SanSebastian (Spain) on September 9, 2009.

COST Action IC0604 researchers have been collaborating with the College ofAmerican Pathologists (CAP), the North American Association of Central CáncerRegistries, and the Center for Disease Control, in order to develop - within WG2 -initiatives that could enhance data and images retrieval and mining for epidemiology orclinical research.

The COST INFO Day event, organized in Spain on 27 November 2009, was animportant dissemination activity. This event was organized by the European ProjectsOffice of the Spanish Ministry of Science and Innovation. COST Action IC0604"EURO-TELEPATH" had the opportunity to present its results.

1.3. COST Action Instriiments

The following list of COST Action activities [6] has been essential for the developmentof the EURO-TELEPATH project:

1.3.1. Meetings

The COST Action can support travel and subsistence for the participation to thefollowing meeting types:• Management Committee (MC) meetings.• Core Group meetings. Smaller group typically composed of Chair, Vice-Chair, and

Working Group Leaders.• Working Group (WG) meetings.• Workshops/Conferences.• Final Conference.

Each year one of the scientific activities of the Action should involve Early StageResearchers, i.e. as any researcher whose career has not yet exceeded 8 years afterachievement of a PhD/doctorate (or similar experience), to strengthen links with eachother and with experienced scientists involved in the management of the Action.

The Working Groups usually consist of a small number of researchers selected bythe MC. Apart from MC members, other researchers from a participating countrycontributing to the achievement of the objectives of the Action are usually invited toparticípate in working groups, either as extemal experts or as invited speakers.

1.3.2. Training Schools

Training Schools within the framework of the Action topic are aimed at widening theknowledge of Action activities, providing intensive training on a new and emerging

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subject, and offering familiarization with unique equipment or know how in one of thelaboratories of the Action.

Training Schools are not intended to provide general training or education. Thoseattending a Training School are typically - but not exclusively - young researchersfrom across Europe. Furthermore, Training Schools may also cover appropriate re-training as part of life-long leaming.

1.3.3. Short-Term Scientific Missions

Short-Term Scientific Missions (STSM) are short exchange visits, aimed atstrengthening the existing networks by allowing scientists to go to an institution orlaboratory in another COST Country to foster collaboration, to leam a new techniqueor to take measurements using instruments and/or methods not available in their owninstitution/laboratory. They are particularly intended for young scientists. An Actionshould normally set up at least 4 STSMs per year.

1.3.4. Dissemination Tools and Publications

The COST Action IC0604 "EURO-TELEPATH" Web site (http://www.conganat.org/eurotelepath) has been working since the start of the action in November 2007. Foractive interchange of data, file repository and messages, we started using a GoogleGroup (cost-IC0604@googlegroups.com). After detailed revisión of Google Terms ofService and PrivacyPolicy, we decidednot using this service, since its gives "Googlealicense to reproduce, adapt, modify, transíate, publish, publicly perform, publiclydisplay and distribute any content which you submit, post or display on or through, theServices." At the end of February 2008 a new service based on the Open Sourcesoftware Mailman, a GNU Mailing List Manager, was started (cost-ic0604@lists.conganat.org). Nowadays, our website contains a presentation andgeneral description of the action (including Action poster), a list of past and ftituremeetings (intemal access to minutes and full presentations), sector news, and a link tointeractive services (mailing list archives and files).

In general, different kinds of dissemination tools and publications can be includedin the Action budget:

1. High-level publications produced by a renowned publisher for high levelpublications (usually books or joumals). This type includes the purchase ofexisting publications and open-access web-based publications follow the sameprocess as printed publications.

2. Printing of conference or workshop proceedings

This book is the Final Action Publication of COST Action IC0604

2. WGl. Pathology Business Modeling

In COST Action IC0604, we have developed a general business process in pathology toanalyzeand specifythe requirements for integrating telepathology in routinediagnosticprocess, education, research, and quality control activities [7,8]. The business processis designed as a best practice model and can be used for discussion and description ofspecific processes in a department [9].

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The current model of business processes in pathology design in COST ActionIC0604 will be presented, discussed and modified according to the requests and inputsfrom the participants. The flexibiüty and usefulness of business process modeHng willbe shown and explained in detail.

WG meetings and STSMs enabled a fruitfiil study comparing notations andpathology processes, mainly using Business Process Modeling Notation (BPMN),Event-driven Process Chains (EPC) and Unified Modeling Language ActivityDiagrams (UML AD). While UML has been developed to provide computer scientistswith graphical expression means for ICT processes, needing the combination of manydifferent diagrams with special notation rules, BPMN focus on the process itself,thereby covering actions and conditions over time. We concluded that BPMN is themodeling notation which is clearer and more understandable to pathologists. EPC isharder for pathologists to read and understand. It is probably because EPC is not aspopular as BPMN, so pathologists are not so familiar with the concept of event drivenprocess.

A full pass at theoretical research, modeling, analysis, simulation implementation,scenario setup, and result evaluation, and, to some extent, presentation was achieved inthe nine working days of STSM at the University of Castilla-La Mancha. There is alack of customizability of the simulation tools on the market. This may change in thefuture. For example, an Open Source discrete event simulator like ns-2 for networkprotocol simulation or [10] might offer the needed flexibility to model the simulationaccurately enough.

The diagnostic process in Pathology has been modeled, consisting of at least threesubprocesses: the routine diagnostic process, the teleconsultation as an additional toolto confirm the diagnosis and the immunohistochemistry (IHC) with the new impact ontherapy. It is decided that IHC and molecular pathology should be considered as aspecial business valué like "Predictive Marker Evaluation". Integration of automatonswas also modeled. Anatomic pathology reporting to public health repositories is alsoconsidered.

3. WG2. Informatics Standards in Pathology

In order to achieve the objective of increasing the use of automation procedures beyond50% in anatomic pathology, we have analyzed device connectivity followingIntegrating the Healthcare Enterprise (IHE) recommendations, including a study of theprevious work done in clinical laboratory (Laboratory Device Automation Profile).Differences between clinical laboratory and anatomic pathology were presented, andthe protocols and formats met in the field of clinical laboratory, that we should considerwere: Transport (e.g. Serial interfaces (RS232c), low leve! protocol ASTM E1381; andLAN interfaces), and Data format (ASTM El394, HL7 [OML, OUL, ORM, ORU]).

In Integrating the Healthcare Enterprises (IHE) Anatomic Pathology TechnicalFramework, "Integration profiles" are real-world situations describing the exchange ofinformation, called transactions, from various functional components of a distributedhealth care environment, called actors. IHE, which has developed in North América,Europe, and Asia, provides implementation guides for transactions by using establishedindustry standards such as DICOM or HL7. The annual defmition cycle of new profilesby users and suppliers—ending in the organization of international platforms ofinteroperability tests (called "connectathons")—confers its unique efficiency,

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transforming basic standards into "plug and play" solutions. Prior integration profilesdeveloped for radiologic imaging have been very successful [11]. We also addressedthe issue of the participation of the Anatomic Pathology Community in otherstandardization organizations such as IHTSDO, OBO Foundry or the JPEG communityin order to take advantage of the most advanced results of these groups (referencebiomedical ontologies, compression algorithms, etc.) [1].

3.1. A Data Modelfor Handling whole Slide Microscopy Images in Picture Archivingand Communication Systems

Extremely large medical images, like virtual slide microscopy ones, are going beyondsome limitations (e.g., a 4Gbyte barrier, caused by 32-bit architecture) of the DICOM(Digital Image Communication in Medicine) standard. Some solutions and trade-offshave been already proposed and included in the DICOM standard or are beingdiscussed (e.g. usage of JPEG2000 image compression standard, JPEG2000 interactiveprotocol (JPIP) and división of images into smaller parts is being discussed, stored thenin a Picture Archiving and Communication System (PACS)). They might lead howeverto the simultaneous implementation of altemative interaction solutions in the samePACS, serving both images of typical size (e.g. radiological) and large size virtual slidemicroscopy images. The following issues are being discussed: a problem ofconstructing a data and interaction model of images within PACS, looking for criteriato assess image content complexity and to enable an efficient división of virtual slidemicroscopy images into tiles; providing both the conventional DICOM services and theimage interchange using JPIP (JPEG2000 interactive protocol) [1] in parallel.

A COST Action IC0604 MC member was present at the DICOM WG26 Meetingin September 2008 in San Diego, California. The main topics discussed during thismeeting have been: a) Including a way of indicating whether any images containprotected health information. b) Acceptance of non-square pixels since not all devicescapture square pixels. c) Basic unit should be a pixel (there was no consensus onmoving to a voxel). d) In a DICOM object. the tile size of a given layer will be fixed. e)It would be perfectly permissible to have múltiple scanned/captured layers in a pyramid,but we expect that the usual case will be capturing only the highest resolution(baseline) information and processing the lower "power" layers from that highresolution layer [12].

3.2. Pathology Informatics Standards Dissemination inside the Pathologist andInformatics Communities

One of the most significant scientific outcome of the COST Action IC0604 is gettingmedical doctors aware of the importance of DICOM, HL7, IHE and other medicalinformatics standards and specifications. On this issue, the consortium has published areview paper in one of the most important joumals in the pathology field [13].

The Anatomic Pathology Reporting to Public Health integration profile wassuccessfully tested during the llth annual IHE North América Connectathon, held on11-15 January 2010 in Chicago. At the lOth annual IHE European Connectathon on 12-16 April at the Cité Mondiale in Bordeaux, France, the Anatomic Pathology GeneralWorkflow profile was successfully demonstrated.. COST Action IC0604 was alsopresent in the IHTSDO (Intemational Health Terminology Standard DevelopmentOrganisation) Conference, 26-30 April 2010, in Copenhagen, Denmark. COST Action

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IC0604 MC Members have been attending DICOM WG26 Pathology meetings.Furthermor

2008 [14].Furthermore, COST IC0604 was presented to the JPEG plenary audience on July 9^^

4. WG3. Images: Analysis, Processing, Retrieval and Management

Comparative studies performed by the group on quantitative automatic andsemiquantitative light microscopy methods used for the immunoreactive cellsrecognition have been the first step in validating the automatic quantification inimmunohistochemistry of the digital pathology (virtual slide - based diagnostics). Therelevance of density and/or distribution of various cells (e.g. neuroendocrine cells)using immunohistochemistry markers need to be studied for a better understanding ofsome inflammatory and neoplastic diseases. Different image analysis methods that canbe performed in static pictures and virtual slides need a consensus.

The impact of image compression on image analysis has been addressed in somepapers by researchers of the consortium [15]. An initiative of the group led tocollaboration with JPEG on a new approach for very large medical images usingAdvanced Image Coding (AIC).

Three training schools on open software for image analysis in pathology have beenorganized between 2009 and 2011. In each training school, about thirty trainees fromabout ten different European countries attended. The main objective of these courseswas providing training in basic image analysis using open source software(measurements / masking / ROI / segmentation / texturing / cell counting / ploidyanalysis, etc.).

5. WG4. Technology and Automation in Pathology

COST Action IC0604 WG4 has reviewed 12 commercial scanning systems, some ofthem still under development. Also, virtual slide viewers and upcoming projects aboutmanaging large pathology images have been studied. After reviewing all existingsolutions, the main actors important to be considered for integrating slide scanners inthe daily workflow of hospitals have been defmed. In general, existing systems allow ahigh quality digitization of pathology microscopic images, although in some casesobtained images may still contain out of focus areas. The main user complaints concerninadequate resolution (over 0.23 microns/pixel may be needed) and the delay inviewers to move between different fields and magnifications.

Digital pathology is a field of increasing interest for both companies and users.There is an ever-increasing demand for pathology-based diagnosis, particularly infields like oncology, nephrology and gastroenterology, mainly due to the demographicshift with a growing number of people getting older. Digital pathology is the solution tothis increasing demand, as the recent launch of two European scanning systems by thebig companies Philips (Pathology Slide Scanner) and Leica (SCN400) demonstrates.Our COST Action has collaborated in the development of these new scanning solutions.

The Hungarian company 3DHistech, with more than ten years' experience indigital pathology has been pioneering this field all the years. They have recentlydeveloped a high throughput whole slide scanner using area sensors, flash lightillumination and solid state light engine.

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A pathology slide scanner contest was organized in 2010, during the GermánPathology Week, and results were presented during the lOth European Congress onTelepathology in Vilnius, Lithuania.

Fast slide digitization with good quality is an essential objective to increaseproductivity of the regular pathologist daily workload. A related collaborative studyhas been performed, which has been presented at the Workshop on "QuantitativeImmunohistochemistry in Digital Pathology" in Warsaw, Poland, on November 28-29,2008 [16].

6. COST Action IC0604 Scientifíc Impact and Future Research Needed

Published papers (see references) and presentations given to intemational congressesshow the high impact of our COST Action in the scientifíc area of pathology andmedical informatics. Pharmaceutical companies and veterinary researchers are veryinterested in our activities as well. Improvements in diagnostics, targeted andpersonalized medicine, and prognosis evaluation are the expected socio-economicbenefíts of this Action.

The main médium term effect of our activities has been the development ofstandards for workflow and image format in Pathology that will allow a rapiddevelopment of new research areas in digital pathology (image analysis, automation)and clinical telemedicine applications in the area of pathology. According to thePubmed database, a signifícant increase of research activities in computing inpathology and telepathology has been observed (until 2000, 294 papers were collected;from 2001 to 2009, 343 papers were found in the PubMed database; only in the last 2years, 257 papers addressing this area can be found in this database).

New companies and business projects related to imaging in Pathology and imageanalysis automation have emerged. For example, Philips has created a special interestgroup in Pathology; the Austrian company TissueGnostics was established in 2003,focusing on research and development in laboratory and software technology, notablyincluding microscopy.

COST Action IC0604 realized that a new area of research based on

nanotechnology could be very important in pathology. In 2010, there were about 3680papers about quantum dots (the first one was published in 1990) in the Pubmeddatabase. Thereof, only 144 refer to the pathology fíeld (the fírst has been published in2002). Initial contacts with other COST Actions working on nanosciences (likeMP0603 and MP0701) were started. Future COST Action dedicated to pathology andtechnology should focus in this fíeld.

References

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[2] C. Daniel C, M.G. Rojo, J. Klossa, V. Della Mea, D. Booker, B.A. Beckwith and T. Schrader T,Standardizing the use of whole slide images in digital pathology, Computerized Medical Imaging andGraphics 35 (2011), 496-505.

[3] M.G. Rojo, C. Daniel, T. Schrader T, Standardization efforts of digital pathology in Europe, Anal CellPathonS {20\2\ 19-23.

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[4] M.G. Rojo, A.M. Castroand L. Gon9alves. COST Action"EuroTelepath": digital pathologyintegrationin electronic health record, includingprimary care centres, Diagnostic Pathology 6 Suppl 1 (2011), S6.

[5] B. Reljin, Z. Milosevi,T. Stoji, I. Reljin, Computer aided system for segmentationand visualizationofmicrocalcifications in digital mammograms. Folia Histochemica et Cytobiologica 47 (2009), 525-532.

[6] COST Vademecum (Part B): Grant System. COST (European Cooperation in Science and Technology).v25/05/2010. Available at: http://www.cost.esf.org/participate/guidelines

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[9] S.S. Cross, T. Dennis, R.D. Start, Telepathology: current status and ftiture prospects in diagnosticYú^io^diihoXogy, Histopatholog}^ 4\ (2002), 91-109.

[10] B. Rücker, Building an open source Business Process Simulation tool with JBoss jBPM. Master's thesis,Stuttgart University of Applied Science, 2008.

[11] C. Daniel, F. Macary, M.G. Rojo, J. Klossa, A. Laurinavicius, B.A. Beckwith, V. Della Mea, Recentadvances in standards for Collaborative Digital Anatomic Pathology, Diagn Pathol 6 Suppl I (2011),SI7. Available at: http://www.diagn0sticpath0l0gv.0rg/c0ntent/6/S1/S17

[12] Minutesfrom the DICOM workinggroup twenty-six(Pathology). September 27, 2008. San Diego, CA.Available at: http://medicaLnema.org/DICOM/minutes/WG-26/2008/2008-09-27/WG-26 2008-09-

[13] C. Daniel, M. García Rojo, K. Bourquard, D. Henín, T. Schrader, V. Della Mea, J. Gilbertson, B.A.Beckwith, Standards to support information systems integration in anatomic pathology, Arch PatholLab Medm (2009), 1841-1849.

[14] JPEG Committee. Poitiers meeting, July 7-11, 2008. Available at: http://www.ipeg.org/newsrel22.html[15] C. López, J. Jaén Martínez, M. Lejeune, P. Escrivá, M.T. Salvado, L.E. Pons, T. Alvaro, J. Baucells, M.

García-Rojo, X. Cugat, R. Bosch, Roundness variation in JPEG images affects the automated processof nuclear immunohistochemical quantification: correction with a linear regression model, HistochemCell Biol 132 (2009), 469-477.

[16] M. García Rojo, G. Bueno, J. Slodkowska, Review of imaging solutions for integrated quantitativeimmunohistochemistry in the Pathology daily practice. Folia Histochem Cytobiol 47 (2009), 349-354.