User-defined functions in the Arden Syntax: An extension proposal.

BACKGROUND: The Arden Syntax is a knowledge-encoding standard, started in 1989, and now in its 10th revision, maintained by the health level seven (HL7) organization. It has constructs borrowed from several language concepts that were available at that time (mainly the HELP hospital information system and the Regenstrief medical record system (RMRS), but also the Pascal language, functional languages and the data structure of frames, used in artificial intelligence). The syntax has a rationale for its constructs, and has restrictions that follow this rationale. The main goal of the Standard is to promote knowledge sharing, by avoiding the complexity of traditional programs, so that a medical logic module (MLM) written in the Arden Syntax can remain shareable and understandable across institutions. OBJECTIVES: One of the restrictions of the syntax is that you cannot define your own functions and subroutines inside an MLM. An MLM can, however, call another MLM, where this MLM will serve as a function. This will add an additional dependency between MLMs, a known criticism of the Arden Syntax knowledge model. This article explains why we believe the Arden Syntax would benefit from a construct for user-defined functions, discusses the need, the benefits and the limitations of such a construct. METHODS AND MATERIALS: We used the recent grammar of the Arden Syntax v.2.10, and both the Arden Syntax standard document and the Arden Syntax Rationale article as guidelines. We gradually introduced production rules to the grammar. We used the CUP parsing tool to verify that no ambiguities were detected. RESULTS: A new grammar was produced, that supports user-defined functions. 22 production rules were added to the grammar. A parser was built using the CUP parsing tool. A few examples are given to illustrate the concepts. All examples were parsed correctly. CONCLUSIONS: It is possible to add user-defined functions to the Arden Syntax in a way that remains coherent with the standard. We believe that this enhances the readability and the robustness of MLMs. A detailed proposal will be submitted by the end of the year to the HL7 workgroup on Arden Syntax.

Work System Characteristics Impacting the Performance and Quality of the Discharge Letter Process.

Studies on the impact of a Health Information Technology seldom consider socio-technical characteristics of the work system in which the technology is implemented. Yet those dimensions may act as hidden variables that could explain the inconsistency of impact studies' results in terms of performance, quality and satisfaction. This paper reports on the identification of those variables in the discharge letter (DL) process. Human Factors experts performed an analysis of the work system of the DL process in 17 medical units. The DL process is composed of three sub-processes running with work system differing according to the distribution of tasks, the technology implemented and the work organization. Hidden variables identified are: verification by the physician, technology's integration, number of editing cycles, physicians' preferences etc. Those variables can be collected automatically or by questionnaire. Statistical analyses will have to be performed to know which variable explain impact indicators.

Quality indicators from laboratory and radiology information systems.

Consequences of the computerization of laboratory and radiology information system (LIS and RIS) are not well documented. The aim of this study was to evaluate the impact of computerization of LIS and RIS of four hospitals on performance and quality of care. The study was divided into three phases. First, the subprocesses and information flows of LIS and RIS were described. Then, a literature review was performed in order to identify the indicators used to assess the impact of computerization. Finally, comparisons were made between 2 hospitals. Using the initial framework, each partner described its process mapping concerning LIS and RIS. The review identified a wide panel of indicators. Only 41 were useful to assess the impact of information systems. For each two by two comparison, lists of relevant indicators have been selected from the identified indicators and according to the process mapping comparison. Two by two comparisons have to be completed. Eventually, these indicators may be integrated in the quality process of hospital information systems.

Preservation of information in terminology transcoding.

Linking interface terminologies (IT) to reference terminologies (RT) in flow of terminologies may allow health information system to be both usable and interoperable. Two French university hospitals worked independently on such a flow from the prescription of lab-test to the display of the corresponding results. The aim of this study was to evaluate the transmission of information in these two hospitals communication. An expert, supported by natural language processing tool, created the gold standard link between the 2 prescription ITs i.e. the terms that share the same meaning. A semantic pathway was defined to allow the mapping of one prescription IT to the other, through LOINC® and SNOMED®, the RT chosen by each hospital, respectively. The capacity of the semantic pathway to identify the correct links was computed. The expert found 218 links between the 2 prescription ITs (containing 580 and 374 terms that are linked to RT). The semantic pathway correctly identifies 96 of these links (44.0% [37.4-50.6]). The recall was not as good as expected, even though the semantic pathway was created in order to maximize it. Using different RT in different hospitals is not an efficient solution. The use of LOINC® seems to be preferable as a RT for prescription.

A guideline-derived model to facilitate the implementation of test-ordering rules within a hospital information system.

The culture of evidence-based practice includes also the field of laboratory medicine. Clinical laboratory expenditure is growing rapidly for various reasons including increased utilization. Delivering decision support to requesters at the point of care is one of the main incentives for implementing laboratory guidelines. Laboratory guidelines were analyzed to extract test-ordering rules. Each rule was explicated in at least one clinical situation with triggers that launch the execution of the implemented rule. The Unified Modeling Language was used to represent the categories of information elements found in the guidelines and underline the information elements that need to be structured and coded in the EHR. These information elements are related to conditions including clinical conditions, habits, family history, demographic information, medical treatments, laboratory tests, and non-laboratory test procedures. Timestamping of each event is also important for implementing laboratory prescription rules. A linkage between the conditions of this model and HL7 RIM was feasible. Use of this model facilitates the implementation of evidence-based test-ordering rules and clarifies the EHR requirements for successful implementation of guidelines.

Implementation and management of a biomedical observation dictionary in a large healthcare information system.

OBJECTIVE: This study shows the evolution of a biomedical observation dictionary within the Assistance Publique Hôpitaux Paris (AP-HP), the largest European university hospital group. The different steps are detailed as follows: the dictionary creation, the mapping to logical observation identifier names and codes (LOINC), the integration into a multiterminological management platform and, finally, the implementation in the health information system. METHODS: AP-HP decided to create a biomedical observation dictionary named AnaBio, to map it to LOINC and to maintain the mapping. A management platform based on methods used for knowledge engineering has been put in place. It aims at integrating AnaBio within the health information system and improving both the quality and stability of the dictionary. RESULTS: This new management platform is now active in AP-HP. The AnaBio dictionary is shared by 120 laboratories and currently includes 50 000 codes. The mapping implementation to LOINC reaches 40% of the AnaBio entries and uses 26% of LOINC records. The results of our work validate the choice made to develop a local dictionary aligned with LOINC. DISCUSSION AND CONCLUSIONS: This work constitutes a first step towards a wider use of the platform. The next step will support the entire biomedical production chain, from the clinician prescription, through laboratory tests tracking in the laboratory information system to the communication of results and the use for decision support and biomedical research. In addition, the increase in the mapping implementation to LOINC ensures the interoperability allowing communication with other international health institutions.

Implementation of a platform dedicated to the biomedical analysis terminologies management.

BACKGROUND AND OBJECTIVES: Assistance Publique - Hôpitaux de Paris (AP-HP) is implementing a new laboratory management system (LMS) common to the 12 hospital groups. First step to this process was to acquire a biological analysis dictionary. This dictionary is interfaced with the international nomenclature LOINC, and has been developed in collaboration with experts from all biological disciplines. In this paper we describe in three steps (modeling, data migration and integration/verification) the implementation of a platform for publishing and maintaining the AP-HP laboratory data dictionary (AnaBio). MATERIAL AND METHODS: Due to data complexity and volume, setting up a platform dedicated to the terminology management was a key requirement. This is an enhancement tackling identified weaknesses of previous spreadsheet tool. Our core model allows interoperability regarding data exchange standards and dictionary evolution. RESULTS: We completed our goals within one year. In addition, structuring data representation has lead to a significant data quality improvement (impacting more than 10% of data). The platform is active in the 21 hospitals of the institution spread into 165 laboratories.

Construction of a dictionary of laboratory tests mapped to LOINC at AP-HP.

We report on the ongoing process implemented at Assistance Publique-Hôpitaux de Paris (AP-HP), the largest hospital system in Europe, to build a common reference for laboratory tests in French with LOINC mappings. At the time of writing, it contained 24,000 tests, covering all fields of biology, in use in 19 AP-HP hospitals, 30% of which had a mapping to LOINC with a peak of over 60% in biochemistry.

Is the volume-outcome relation still an issue in the era of PCI with systematic stenting? Results of the greater Paris area PCI registry.

AIMS: In acute myocardial infarction (AMI), primary percutaneous transluminal angioplasty (PTCA) is the preferred option when it can be performed rapidly. Because of the limited access to high PTCA volume centres in some areas, it has been suggested that PTCA could be performed in low-volume centres on AMI patients. Little data exist on the validity of this strategy in modern era PTCA. METHODS AND RESULTS: The Greater Paris area comprises 11 million inhabitants and accounts for 18% of the French population. In 2001, the hospital agency of the Greater Paris area set up a registry of all PTCAs performed in this region. Data from 2001 and 2002 was analysed. Hospitals performing <400 PTCAs per year were classified as low-volume. A case-control analysis (propensity score) compared in-hospital mortality in low- and high-volume centres. A total of 37 848 angioplasty procedures were performed in 44 centres during the study period; 24.7% were performed in low-volume centres. A non-statistically significant trend towards reduced in-hospital mortality was noted in high-volume centres as opposed to low-volume centres: 2.01 vs. 2.42%, P = 0.057. In-hospital mortality rates were significantly different in the sub-group of emergency procedures: 6.75% in high- vs. 8.54% in low-volume centres, P = 0.028. No difference was noted between low- and high-volume centres in non-emergency procedures (0.62 vs. 0.62%, P = 0.99). CONCLUSION: In the era of modern stenting, a clear inverse relationship exists between hospital PTCA volume and in-hospital mortality after emergency procedures. Tolerance of low-volume thresholds for angioplasty centres with the purpose of providing primary PTCA in AMI should not be recommended, even in underserved areas.

Comment on "The cochlear amplifier as a standing wave: 'squirting' waves between rows of outer hair cells?" J. Acoust.Soc. Am. 116, 1016-1024.

Bell and Fletcher [J. Acoust. Soc. Am. 116, 1016-1024 (2004)] proposed that one of the functions of activity of the outer hair cells (OHCs) might be a fluid-pumping action generating lateral fluid flow in the gap between the reticular membrane and the tectorial membrane and they supplied mathematical and descriptive justification for their theory which drew heavily upon the postulation (Gold, 1948) of the need for an active mechanism in the mammalian cochlea. In the 1970s there had been considerable speculation about how the inner hair cell (IHC) stereocilia are stimulated, whether they are stimulated in proportion to basilar membrane displacement or velocity or both, and whether the velocity dependence is due to subtectorial fluid flow. In 1977 experiments were conducted to investigate the possibility of subtectorial fluid flows using a dye as tracer. The work was not reported because it had been conducted at a time when visual observation of cochlear function had fallen out of favor in comparison with the more sensitive techniques thought necessary to observe submicroscopic phenomena, and secondly because it yielded a negative result. The essential details of those experiments are reported here to note for the record the extent to which this elaborate idea has already been tested.

Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d'Etude des Lymphomes de l'Adulte programs.

PURPOSE: Epidemiologic studies show an association between hepatitis C virus (HCV) and B-cell non-Hodgkin's lymphoma (NHL). Treatment and outcome of patients with diffuse large-cell lymphoma (DLCL) and HCV infection are still a matter of debate. PATIENTS AND METHODS: We studied the HCV-positive patients with B-cell DLCL included in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) programs LNH 93 and LNH 98. They were compared with the other patients with DLCL included in these programs. HCV infection prevalence was 0.5% (26 of 5,586 patients). RESULTS: Histologic types of HCV-positive DLCL were more frequently transformed from low-grade lymphoma than DLCL in HCV-negative patients (32% v 6%, P = .02). This is also supported by more frequent spleen involvement in HCV-positive patients (46% v 17%, P < .001). HCV-positive patients had more frequently elevated lactate dehydrogenase levels than other patients (77% v 55%, P = .02). Outcome of HCV-positive patients was poorer for overall survival (P = .02) but not for event-free survival (P = .13). After matching on age and prognosis factors, at 2 years of follow-up, the overall survival was 56% (95% CI, 33% to 76%) among HCV-positive patients, versus 80% (70% to 89%), and the event-free survival was 53% (33% to 72%) versus 74% (64% to 84%). The short-term hepatic toxicity of chemotherapy was strongly increased among HCV-positive patients. After exclusion of the two subjects with chronic hepatitis B virus infection, the overall proportion of subjects undergoing hepatic toxicity was 65% (15 of 23 patients). CONCLUSION: HCV-positive patients with DLCL differ from other patients both at presentation and during chemotherapy. Specific protocols evaluating antiviral therapy should be designed for these patients.

Mortality prediction using SAPS II: an update for French intensive care units.

INTRODUCTION: The standardized mortality ratio (SMR) is commonly used for benchmarking intensive care units (ICUs). Available mortality prediction models are outdated and must be adapted to current populations of interest. The objective of this study was to improve the Simplified Acute Physiology Score (SAPS) II for mortality prediction in ICUs, thereby improving SMR estimates. METHOD: A retrospective data base study was conducted in patients hospitalized in 106 French ICUs between 1 January 1998 and 31 December 1999. A total of 77,490 evaluable admissions were split into a training set and a validation set. Calibration and discrimination were determined for the original SAPS II, a customized SAPS II and an expanded SAPS II developed in the training set by adding six admission variables: age, sex, length of pre-ICU hospital stay, patient location before ICU, clinical category and whether drug overdose was present. The training set was used for internal validation and the validation set for external validation. RESULTS: With the original SAPS II calibration was poor, with marked underestimation of observed mortality, whereas discrimination was good (area under the receiver operating characteristic curve 0.858). Customization improved calibration but had poor uniformity of fit; discrimination was unchanged. The expanded SAPS II exhibited good calibration, good uniformity of fit and better discrimination (area under the receiver operating characteristic curve 0.879). The SMR in the validation set was 1.007 (confidence interval 0.985-1.028). Some ICUs had better and others worse performance with the expanded SAPS II than with the customized SAPS II. CONCLUSION: The original SAPS II model did not perform sufficiently well to be useful for benchmarking in France. Customization improved the statistical qualities of the model but gave poor uniformity of fit. Adding simple variables to create an expanded SAPS II model led to better calibration, discrimination and uniformity of fit, producing a tool suitable for benchmarking.

Were less disabled patients the most affected by 2003 heat wave in nursing homes in Paris, France?

OBJECTIVE: To analyse the change of mortality rates (MRs) and their contributing medical factors among nursing home patients during the 2003 heat wave in France. METHODS: A retrospective observational study was conduced in all nursing homes of the Assistance-Publique-Hôpitaux de Paris (AP-HP), the French largest public hospital group. All AP-HP nursing home patients (4,403) who were institutionalized in May, 2003, were concerned. The MRs of patients between three periods (before, during and after the August 2003 heat wave period) were compared according to their demographic characteristics, level of dependence and medical condition. RESULTS: The MR increased from 2.2 per cent persons month (ppm) (1.9-2.4) before heat wave up to 9.2 ppm (8.0-10.4) during heat wave and back to 2.4 ppm (2.2-2.7) after heat wave. MRs before heat wave were higher among highly dependent patients compared to those less dependent [mortality rate ratio (MRR) = 2.66 (1.69-4.21)]. This difference disappeared during the heat wave [MRR = 1.28 (0.91-1.81)] and appeared again after heat wave [MRR = 2.21 (1.52-3.23)]. The same pattern was observed for several medical conditions, such as severe malnutrition or swallowing disorders. CONCLUSION: These results suggest that medical care during heat wave has been directed towards more fragile patients, helping to limit deaths in this group. Less frail patients made the largest contribution to excess mortality during the heat wave. During extreme weather conditions, specific attention should be paid not only to frail persons, but to all the elderly community.

[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome.

Assessment of early therapeutic response using metabolic imaging is potentially useful to determine prognosis in aggressive lymphoma. Between January 2000 and January 2004, 90 patients with newly diagnosed aggressive lymphoma (median age 53 years, 94% diffuse large B-cell) were prospectively explored with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) prior to induction chemotherapy, after 2 cycles ("early PET"), and after induction completion. Therapeutic response was evaluated using conventional diagnostic methods at 4 cycles. Induction treatment with an anthracycline-containing regimen was administered to all patients, associated with rituximab in 41%. According to the International Prognostic Index (IPI), 37 patients and 53 patients belonged to the lower- and higher-risk groups, respectively. At midinduction, "early PET" was considered negative in 54 patients and positive in 36. After completion of induction, 83% of PET-negative patients achieved complete remission compared with only 58% of PET-positive patients. Outcome differed significantly between PET-negative and PET-positive groups; the 2-year estimates of event-free survival reached 82% and 43%, respectively (P < .001), and the 2-year estimates of overall survival reached 90% and 61%, respectively (P = .006). Predictive value of "early PET" was observed in both the lower-risk and higher-risk groups, indicating prognostic independence from the IPI. Therefore, FDG-PET should be an early guide to first-line strategies in aggressive lymphoma.

ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma.

BACKGROUND: Chemoradiotherapy is standard treatment for localized aggressive lymphoma. To determine the optimal therapy for nonelderly persons with low-risk localized lymphoma, we conducted a randomized trial comparing chemoradiotherapy with chemotherapy alone. METHODS: Previously untreated patients less than 61 years old with localized stage I or II aggressive lymphoma and no adverse prognostic factors according to the International Prognostic Index were randomly assigned to three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (329 patients) or chemotherapy alone with dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus sequential consolidation (318 patients). RESULTS: With a median follow-up of 7.7 years, event-free and overall survival rates were significantly higher in the group given chemotherapy alone than in the group given CHOP plus radiotherapy (P<0.001 and P=0.001, respectively). The five-year estimates of event-free survival were 82 percent (95 percent confidence interval, 78 to 87 percent) for patients receiving chemotherapy alone and 74 percent (95 percent confidence interval, 69 to 78 percent) for those receiving chemoradiotherapy. The respective five-year estimates of overall survival were 90 percent (95 percent confidence interval, 87 to 93 percent) and 81 percent (95 percent confidence interval, 77 to 86 percent). In a multivariate analysis, event-free and overall survival rates were affected by treatment group, independently of tumor stage and the presence or absence of bulky disease. CONCLUSIONS: In patients under 61 years of age, chemotherapy with three cycles of ACVBP followed by sequential consolidation is superior to three cycles of CHOP plus radiotherapy for the treatment of low-risk localized lymphoma.

CD10 expression in diffuse large B-cell lymphomas does not influence survival.

CD10 expression is considered as a marker of centrofollicular-derived diffuse large B-cell lymphomas (DLBCL). The aim of our study was to determine retrospectively among 98 patients with DLBCL, enrolled in the LNH93 trial of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and homogeneously treated with high-dose cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like regimen [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP)], the expression of CD10 using immunohistochemistry and its correlation with morphological features and clinical parameters. Of the 98 patients studied, 33 (34%) expressed CD10. There was no correlation among clinical parameters, International Prognostic Index risk groups and CD10 expression, with the exception of lactic dehydrogenase levels, which were lower in CD10-negative cases (P=0.005). There was no significant correlation between CD10 expression and morphological subtyping of DLBCL. Indeed, centrofollicular-derived DLBCL may present with numerous immunoblasts or as an immunoblastic lymphoma. Overall survival rate and event-free survival were not significantly different according to CD10 expression (P=0.44 and P=0.34 respectively). Therefore, it appears that CD10 expression does not influence survival or event-free survival in DLBCL.

Measuring performance in health care: case-mix adjustment by boosted decision trees.

OBJECTIVE: The purpose of this paper is to investigate the suitability of boosted decision trees for the case-mix adjustment involved in comparing the performance of various health care entities. METHODS: First, we present logistic regression, decision trees, and boosted decision trees in a unified framework. Second, we study in detail their application for two common performance indicators, the mortality rate in intensive care and the rate of potentially avoidable hospital readmissions. RESULTS: For both examples the technique of boosting decision trees outperformed standard prognostic models, in particular linear logistic regression models, with regard to predictive power. On the other hand, boosting decision trees was computationally demanding and the resulting models were rather complex and needed additional tools for interpretation. CONCLUSION: Boosting decision trees represents a powerful tool for case-mix adjustment in health care performance measurement. Depending on the specific priorities set in each context, the gain in predictive power might compensate for the inconvenience in the use of boosted decision trees.

Bone marrow histological patterns can predict survival of patients with grade 1 or 2 follicular lymphoma: a study from the Groupe d'Etude des Lymphomes Folliculaires.

The influence of bone marrow biopsy (BMB) histology on prognosis and management of follicular lymphomas (FL) remains controversial. A total of 390 patients with grade 1 or 2 FL were prospectively included in the multicentric Groupe d'Etude des Lymphomes Folliculaires trial and their BMB reviewed in order (i) to quantify the ratio of lymphomatous foci (LFo) area to that of BMB size (LFo/BMB), (ii) to determine the BMB patterns for a practical grading of marrow infiltration, (iii) to assess the intra- and inter-observer reproducibility of this grading and (iv) to analyse this grading on event-free (EFS) and overall survival (OS), using univariate and multivariate analyses. A total of 267 patients (68%) had BMB involvement, with inter- and intra-observer reproducibility for classifying the patterns of involvement of 91 and 96%, respectively. Uni- and multivariate analyses demonstrated the adverse influence of (i) a ratio of LFo/BMB > or = 0.1, i.e. three or four nodules/medullary space or > or = 1 nodule + foci of diffuse involvement on EFS (P = 0.03) and (ii) two different histological patterns in the same BMB on EFS (P = 0.004) and OS (P = 0.001). This latter finding was only significant in patients with a high tumour burden and remained significant in multivariate analysis. These results indicate that BMB histology can predict survival of FL patients with a high tumour burden, and may help in defining their treatment.

Hearing loss and perceptions of noise in the workplace among rural Australians.

OBJECTIVE: To compare measured hearing levels of individuals regularly exposed to noise in their workplace to self-reported and family-reported hearing loss. To compare the attitudes and preventative actions adopted by individuals who are more aware of the potential for hearing loss to less aware individuals. DESIGN: The project examined the perceptions of rural workers concerning noise, noise exposure and hearing. The subjects completed a 'Noise at Work' questionnaire and some demographic data at the time of audiometric testing. SETTING: The subjects were recruited when attending their rural health clinic for audiometric testing. PARTICIPANTS: Participants comprised 113 men and 23 women (20-65 years, mean = 39.6, SD = 11.4) working across a range of activities at different levels in their workplaces. The range in current employment was from 0.5 to 45 years (mean = 13.8, SD = 10.7). RESULTS: Hearing tests were compared with perceptions of noise annoyance, hearing damage risk and preventative action. Self- and family-reported hearing loss and conversational difficulties in noise correlated well with measured audiograms. Perceptions of workplace noise tended to be more positive if people felt they had hearing problems. There was no difference in preventative action between those who did and did not feel they had hearing problems. Both groups rated barriers to action and lack of self-efficacy in a similar negative way. CONCLUSIONS: There is a need for specific training to ensure that rural workers have skills to take more positive action in reducing noise exposure at work.

TiA1 in advanced-stage classical Hodgkin's lymphoma: no prognostic impact for positive tumour cells or number of cytotoxic cells.

No reliable marker still exists for predicting those patients with Hodgkin's lymphoma (HL) who may experience a fatal outcome. Among the factors tested in the literature, it has been suggested that the number of activated cytotoxic T cells may represent a prognostic marker in HL. In 244 samples from patients with stage-IIIB/IV HL issued from the GELA H89 trial, we have analysed TiA1 expression on Reed Sternberg (RS) cells as well as the percentage of positive reactive lymphocytes. There were 34 cases (13.7%) that showed TiA1 expression on tumour cells; whereas, in 32 cases (13.1%), TiA1-positive reactive lymphocytes represented more than 30% of the reactive lymphocytes. LMP-1 was found co-expressed with TiA1 in 10 of the 22 positive cases tested. Our study confirms that a subset of classical HL expresses cytotoxic proteins, with occasional co-expression of CD20. In stage-IIIB/IV disease, neither TiA1 expression by RS cells nor a high percentage of TiA1-positive reactive lymphocytes have a prognostic impact on outcome.