Combining dynamic and static robotic telepathology: a report on 184 consecutive cases of frozen sections, histology and cytology.

The aim of this paper is to describe the experiments carried out to evaluate the diagnostic efficacy of a dynamic-robotic telepathology system for the delivery of pathology services to distant hospitals. The system provides static/dynamic features and the remote control of a robotized microscope over 4 ISDN lines. For evaluation purposes, 184 consecutive cases of frozen sections (60), gastrointestinal pathology (64), and urinary cytology (60) have been diagnosed at a distance using the system, and the telediagnosis obtained in this way has been compared with the traditional microscopic diagnosis. Diagnostic agreement ranged from 90% in urinary cytology to 100% in frozen sections. The results obtained suggest that such a system can be considered a useful tool for supporting the pathology practice in isolated hospitals.     

Experience with a dynamic inexpensive video-conferencing system for frozen section telepathology.

AIM: To evaluate the feasibility of an inexpensive, generally applicable video-conferencing system for frozen section telepathology (TP). METHODS: A commercially widely available PC-based dynamic video-conferencing system (Picture-Tel LIVE, model PCS 100) has been evaluated, using two, four and six ISDN channels (128-384 kilobits per second (kbs)) bandwidths. 129 frozen sections have been analyzed which were classified by TP as benign, uncertain (the remark probably benign, or probably malignant was allowed), malignant, or not acceptable image quality. The TP results were compared with the original frozen section diagnosis and final paraffin diagnosis. RESULTS: Only 384 kbs (3 ISDN-2 lines) resulted in acceptable speed and quality of microscope images, and synchronous image/speech transfer. In one of the frozen section cases (0.7%), TP image quality was classified as not acceptable, leaving 128 frozen sections for the analysis. Five of these cases were uncertain by TP, and also deferred by frozen section procedure (FS). One more benign and three malignant FS cases were classified as uncertain by TP. Three additional cases were uncertain by FS, but benign according to TP (in agreement with the final diagnosis). In one case, FS diagnosis was uncertain but TP was malignant (in agreement with the final diagnosis). Thus, test efficiency (i.e., cases with complete agreement) was 120/128 (93.8%, Kappa = 0.88) between FS and TP. Sensitivity was 93.5%, specificity 98.6%, positive and negative predictive values were 97.7% and 96.0%. Between TP and final diagnosis agreement was even higher. More importantly, there was not a single discrepancy as to benign-malignant. Moreover, there was a clear learning effect: 5 of the 8 FS/TP discrepancies occurred in the first 42 cases (5/42 = 11.9%), the remaining 3 in the following 86 cases (3/86 = 3.5%). DISCUSSION: The results are encouraging. However, TP evaluation is time-consuming (5-15 min for one case instead of 2-4 min although speed went up with more experience) and is more tiring. The system has the following technical drawbacks: no possibility to point at objects or areas of interest in the life image at the other end, resolution (rarely) may become suboptimal (blocky), storage of images evaluated (which is essential for legal reasons) is not easy and no direct control of a remote motorized microscope. Yet, all users were positive about the system both for telepathology and personal contact by video-conferencing. CONCLUSION: With a relatively simple videoconferencing system, accurate dynamic telepathology frozen section diagnosis can be obtained without false positive or negative results, although a limited number of uncertain cases will have to be accepted.     

Current experiences with internet telepathology and possible evolution in the next generation of Internet services.

The last five years experience has definitely demonstrated the possible applications of the Internet for telepathology. They may be listed as follows: (a) teleconsultation via multimedia e-mail; (b) teleconsultation via web-based tools; (c) distant education by means of World Wide Web; (d) virtual microscope management through Web and Java interfaces; (e) real-time consultations through Internet-based videoconferencing. Such applications have led to the recognition of some important limits of the Internet, when dealing with telemedicine: (i) no guarantees on the quality of service (QoS); (ii) inadequate security and privacy; (iii) for some countries, low bandwidth and thus low responsiveness for real-time applications. Currently, there are several innovations in the world of the Internet. Different initiatives have been aimed at an amelioration of the Internet protocols, in order to have quality of service, multimedia support, security and other advanced services, together with greater bandwidth. The forthcoming Internet improvements, although induced by electronic commerce, video on demand, and other commercial needs, are of real interest also for telemedicine, because they solve the limits currently slowing down the use of Internet. When such new services will be available, telepathology applications may switch from research to daily practice in a fast way.     

Legal aspects of telepathology.

In some legal surroundings telepathology is considered a breach of registrational barriers. The recommendation of the G 8 states in Europe for required legislation in telemedicine suggests to recognise that the localization of the remote health care professional defines the site not only of licensure but also of liability. This approach must be considered helpful, since it can solve many problems brought about by the doubtful results of private international law and conventions like the European Union (EU) and Lugano Convention. Under today's conditions in private international law it must be considered essential to agree upon a choice of law and stipulate a court of jurisdiction when doing telepathology. However, the opposing aims of insuring the patients claims and avoiding jurisdictions that exceed the local expectations of the medical professional must be reconciled. Data protection and data security are other crucial topics that require attention. Generally speaking, the principles of minimum data exchange, anonymity, pseudonymity and cryptography must be established as a basis for all telepathology procedures. Only when personal data is needed, its use can be legitimated. Written consent of the patient is advised. To guarantee a cross-border security level the regulations of the EU-Data Protection Directive need to be transformed into national law. In practise, cross-border dataflow shall only take place where the security level can be maintained even within the other country. Finally, reimbursement questions must be answered to establish a sound economical basis for telepathology. The spatial distance between the participants may yield the question, whether the service has been rendered to an extent necessary and sufficient for reimbursement. If reimbursement takes place on a cross-border or cross-regional level, severe disturbances of the health systems can occur. Regulation schemes or treaties need therefore to be developed to avoid such disturbances and encompass mutual standards of care as well as methods to balance reimbursement.     

Acceptance of telepathology in daily practice.

The availability of pathology services differs greatly in our environment. Although pathology would be especially suitable for being practised at a distance by transporting digital image information, the spread of telepathology into everyday work still is relatively slow. The article describes the situation of diffusion of this innovative technology by reviewing the literature and discussing this in context to data based on questionnaires dealing with the acceptance of telepathology. The current situation of telepathology can be discussed by five items for innovation spead: (1) communication and influence; (2) economic costs and benefits; (3) knowledge barriers and learning; (4) feasibility of techniques offered for the demands of the users; (5) clarification of the legal status and other factors concerning international collaboration. All these head lines do not represent realistic obstacles for the more widespread use of telepathology. The real drawbacks may therefore be found behind certain professional habits of pathologists. The most important causes may be that (a) telediagnosis is not as easy as it may seem at the first glance; (b) telepathology is seen as a potential highway to a world-wide competition of pathology service providers. As soon as these mostly unjustified prejudices are corrected and telepathology is percepted as additional technique in pathology, it will become a diagnostic tool as common and as useful as the telephone.     

Reliability of telepathology for frozen section service.

One of the most promising applications of telepathology (pathology at a distance by electronic transmission of images in pathology) is frozen section diagnosis, especially because by means of this tool operations requiring an intraoperative histopathological diagnosis are feasible at hospitals without a pathologist on-site. For the introduction of this diagnostic tool into pathologist's daily practice the evidence of its diagnostic accuracy comparable to that of the conventional frozen section diagnosis is crucial. For this purpose the literature on the diagnostic accuracy of telepathological frozen section diagnosis was reviewed. In a metaanalysis these studies and reports, in which a total of more than 1290 cases had been examined, showed a slightly lower overall diagnostic accuracy (of the telepathological frozen section diagnosis) of about 0.91 than the conventional frozen section diagnosis with an average accuracy of about 0.98 found in an analysis of several studies (on frozen section diagnosis of different organs). This difference is at least predominantly caused by a higher rate of deferred and false negative frozen section diagnoses in the telepathological method, while the specificity of both methods, each more than 0.99 was not significantly different. In conclusion, the introduction of a telepathological frozen section diagnosis for hospitals without an acceptable access to a pathologist is justifiable already at the current state of the technological development especially when considering the advantages (time saving, reduction in costs) compared to the alternative of surgical interventions without access to an intraoperative diagnosis.     

Recent developments and present status of telepathology.

Telepathology which is the diagnostic work of a pathologist at a distance has been developed to routine application within the last ten years. It can be classified in relation to application, technical solutions, or performance conditions. Diagnostic pathology performance distinguishes primary diagnosis (for example, frozen section statement) from secondary diagnosis (for example, expert consultation) and quality assurance (diagnostic accuracy, continuous education and training). Applications comprise (a) frozen section service; (b) expert consultations; (c) remote control measurements; and (d) education and training. The technical solutions distinguish active (remote control, live imaging) systems from passive (conventional microscope handling, static imaging), and the performance systems with interactive (on-line, live imaging) use from those with passive (offline, static imaging) practice. Intra-operative frozen section service is mainly performed with remote control systems; whereas expert consultations and education/training are commonly based upon Internet connections with static imaging in an off-line mode. The image quality, transfer rates, and screen resolution of active and passive telepathology systems are sufficient for an additional or primary judgment of histological slides and cytological smears. From the technical point of view, remote control telepathology requires a fast transfer and at least near on-line judgement of images, i.e., image acquisition, transfer and presentation can be considered one performance function. Thus, image size, line transfer rate and screen resolution define the practicability of the system. In expert consultation, the pixel resolution of images and natural color presentation are the main factors for diagnostic support, whereas the line transfer rate is of minor importance. These conditions define the technical compartments, especially size and resolution of camera and screen. The performance of commercially available systems has reached a high quality standard. Pathologists can be trained in a short time and use the systems in a routine manner. Several telepathology systems have been implemented in large Institutes of Pathology which serve for frozen section diagnosis in small hospitals located in the local area. In contrast, expert consultation is mainly performed with international connections. There is a remarkable increase of expert consultations by telepathology according to the experiences of the Armed Forces Institute of Pathology or the Department of Pathology, Thoraxklinik, Heidelberg. In expansion of these experiences, a "globalization" of telepathology can be expected. Telepathology can be used to shrink the period necessary for final diagnosis by request for diagnostic assistance to colleagues working in appropriate related time zones. Telepathology is, therefore, not a substitute of conventional diagnostic procedures but a real improvement in the world of pathology.     

Diagnosis of congenital heart malformations--possibilities for the employment of telepathology.

GOAL: In a study of 10 autopsy cases with congenital cardiac malformations we investigated whether obtaining a second opinion by means of telepathology could satisfy quality standards for the diagnosis of cardiac malformations and what the advantages and disadvantages of such a procedure might be. MATERIAL: The investigatory samples were 10 formalin-fixed hearts with complex malformations from 9 fetuses and one newborn on which autopsies had been performed at the Pathological Institute of the Charité Hospital. The requests for a second opinion, which included text and image data, were sent in the form of Microsoft PowerPoint presentations to 5 experts in 4 countries. Per case the number of images that were sent was between 3 and 7. The size of the files was between 439 and 942 kb. The time required for preparation of the cases for sending them to the specialists was between 1 and 2 hours: this encompassed the time for putting the notation on the images, compressing them, creating a file that included both the images and the clinical data and then sending the case file. RESULTS: All 10 cardiac malformations were correctly identified. In 8 of the 10 cases at least one expert had questions. After these questions had been answered and further images had been sent final correct diagnoses were made in all cases. All experts said that the quality of the images was very good. Use of a standardized findings questionnaire, which also included the marking of anatomic structures and of pathological findings in the images, proved useful. Standardized findings forms facilitate orientation during interpretation of the cases and should be used generally to avoid misunderstandings in telepathological communication. CONCLUSIONS: In general it is possible to obtain an effective and reliable diagnosis of congenital heart malformations by means of telepathology. It is far quicker to get a second opinion by this means than by conventional means.     

Informational aspects of telepathology in routine surgical pathology.

Application of computer and telecommunication technology calls serious challenges in routine diagnostic pathology. Complete data integration, fast access patients' data to usage of diagnosis thesaurus labeled with standardized codes and free text supplements, complex inquiry of the data contents, data exchange via teleconsultation and multilevel data protection are required functions of an integrated information system. Increasing requirement for teleconsultation transferring a large amount of multimedia data among different pathology information systems raises new questions in telepathology. Creation of complex telematic systems in pathology requires efficient methods of software engineering and implementation. Information technology of object-oriented modeling, usage of client server architecture and relational database management systems enables more compatible systems in field of telepathology. The aim of this paper is to present a practical example how to unify text based database, image archive and teleconsultation in a frame of an integrated telematic system and to discuss the main conceptual questions of information technology of telepathology.     

Technical aspects of telepathology with emphasis on future development.

Pathology undergoes presently changes due to new developments in diagnostic opportunities and cost saving efforts in health care. Out of the wide field of telepathology the paper selects three prototype applications: telepathology in teleeducation, expert advice for preselected details of a slide and finally telepathology for remote diagnosis. The most challenging field for remote diagnosis is the application in the frozen section scenario. The paper starts with the mental experiment to map conventional procedures to counterparts in telepathology. Technical opportunities and economical restrictions of telepathology equipment are discussed with respect to the components: electronic camera, display devices, haptic sensors and displays, available telecommunication channels and telepathology software. As an example and for illustration of the state of the art for an advanced telemicroscopy system able to perform remote frozen section diagnosis, the HISTKOM equipment is presented in more details. The section concerning future developments regards the aspects of the acceptance by tentative users, legal aspects, costs and affordability of equipment, the market for equipment components and the adequate telecommunication services. Further is regarded the mutual influence of properties of existing systems and application experiences gained with them on the next generation of equipment and application software. Conclusions and references close the paper.     

Cellular senescence and the analysis of generation time distributions.

Generation time analysis by time lapse cinematography is an important method for investigating cellular senescence in culture, but its interpretation is complicated by several types of bias and artifact, including small sample size, cut-off bias, changes in global growth rate, and phase of the population growth cycle. When these factors are considered, interpretation of the data base used by previous investigators changes considerably, and does not reveal any differences in growth behavior between middle and late passage WI-38 cells. Nor does it support the transition probability theory either of cell cycle transit or of culture senescence.     

Comparison of different telepathology solutions for primary frozen section diagnostic.

In a retrospective study on a set of 125 cases we compared the following three telepathology solutions for primary frozen section diagnosis: ATM-TP (connection via ATM), TPS 1.0 (connection via LAN) and TELEMIC (connection via Internet), which represent different concepts of telepathological procedures. A set of 125 routine frozen sections (breast) was selected from the Charité cases of the year 1999. Four experienced pathologists diagnosed retrospectively all of these cases using the ATM-TP and TPS systems and 53 of them with the TELEMIC system. Using the ATM-TP we recorded no false positive (0%), 4 false negative (3.2%) and 4 deferred (3.2%) cases. Using the TPS we recorded no false positive (0%), 4 false negative (3.2%) and 4 deferred (3.2%) cases. Using the TELEMIC we recorded in 53 cases no false positive (0%), no false negative (0%) and 16 deferred (30.2%) cases. The average time of 2.2 minutes per case using ATM-TP is also short enough for routine frozen section diagnostic. This is also true for the TPS system with 7.2 minutes per case.     

Linear systems approach to analysis of complex dynamic behaviours in biochemical networks

Central functions in the cell are often linked to complex dynamic behaviours, such as sustained oscillations and multistability, in a biochemical reaction network. Determination of the specific mechanisms underlying such behaviours is important, e.g. to determine sensitivity, robustness, and modelling requirements of given cell functions. In this work we adopt a systems approach to the analysis of complex behaviours in intracellular reaction networks, described by ordinary differential equations with known kinetic parameters. We propose to decompose the overall system into a number of low complexity subsystems, and consider the importance of interactions between these in generating specific behaviours. Rather than analysing the network in a state corresponding to the complex non-linear behaviour, we move the system to the underlying unstable steady state, and focus on the mechanisms causing destabilisation of this steady state. This is motivated by the fact that all complex behaviours in unforced systems can be traced to destabilisation (bifurcation) of some steady state, and hence enables us to use tools from linear system theory to qualitatively analyse the sources of given network behaviours. One important objective of the present study is to see how far one can come with a relatively simple approach to the analysis of highly complex biochemical networks. The proposed method is demonstrated by application to a model of mitotic control in Xenopus frog eggs, and to a model of circadian oscillations in Drosophila. In both examples we are able to identify the subsystems, and the related interactions, which are instrumental in generating the observed complex non-linear behaviours.     

Non-linear dynamic phenomena in open reconstituted enzyme systems.

The dynamic pattern of an open reconstituted in-vitro enzyme system containing phosphofructokinase, pyruvate kinase and adenylate kinase has been investigated. The approach is experimentally based on a stirred flow-through reactor. Stationary concentrations of phosphofructokinase and pyruvate kinase are maintained by entrapment in polyacrylamide gel particles. The results fit to a theoretical model based on the initial kinetic responses of the enzymes involved. An S-shaped steady state input characteristic for fructose 6-phosphate has been experimentally obtained.