Reconstruction of in-situ porosity and porewater compositions of low-permeability crystalline rocks: Magnitude of artefacts induced by drilling and sample recovery.

Geological site characterisation programmes typically rely on drill cores for direct information on subsurface rocks. However, porosity, transport properties and porewater composition measured on drill cores can deviate from in-situ values due to two main artefacts caused by drilling and sample recovery: (1) mechanical disruption that increases porosity and (2) contamination of the porewater by drilling fluid. We investigated the effect and magnitude of these perturbations on large drill core samples (12-20 cm long, 5 cm diameter) of high-grade, granitic gneisses obtained from 350 to 600 m depth in a borehole on Olkiluoto Island (SW Finland). The drilling fluid was traced with sodium-iodide. By combining out-diffusion experiments, gravimetry, UV-microscopy and iodide mass balance calculations, we successfully quantified the magnitudes of the artefacts: 2-6% increase in porosity relative to the bulk connected porosity and 0.9 to 8.9 vol.% contamination by drilling fluid. The spatial distribution of the drilling-induced perturbations was revealed by numerical simulations of 2D diffusion matched to the experimental data. This showed that the rims of the samples have a mechanically disrupted zone 0.04 to 0.22 cm wide, characterised by faster transport properties compared to the undisturbed centre (1.8 to 7.7 times higher pore diffusion coefficient). Chemical contamination was shown to affect an even wider zone in all samples, ranging from 0.15 to 0.60 cm, in which iodide enrichment was up to 180 mg/kg water, compared to 0.5 mg/kg water in the uncontaminated centre. For all samples in the present case study, it turned out that the magnitude of the artefacts caused by drilling and sample recovery is so small that no correction is required for their effects. Therefore, the standard laboratory measurements of porosity, transport properties and porewater composition can be taken as valid in-situ estimates. However, it is clear that the magnitudes strongly depend on site- and drilling-specific factors and therefore our results cannot be transferred simply to other locations. We recommend the approach presented in this study as a route to obtain reliable values in future drilling campaigns aimed at characterising in-situ bedrock properties.

IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients.

This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/m2/wk x 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/m2/wk x 4) against MCL and SLL/CLL appeared to be limited, however.

A comprehensive knowledge-based system for laboratory hematology.

The Coulter FACULTY knowledge-based systems, Professor Petrushka for peripheral blood interpretation, Professor Fidelio for flow cytometry immunophenotyping and Professor Belmonte for bone marrow reporting, have been installed in several hospitals in Spain, Portugal and the United Kingdom. In Spain and Portugal, the systems are part of the IZASA-Coulter CITOTECA workstation, which includes a video camera for capturing microscopic images and a networkable laboratory information system supporting color reports. At the Royal Hospitals Trust (St. Bartholomew's Hospital and The Royal London Hospital, London, UK), networked workstations are available and the system is used daily to generate bone marrow reports in the hematology laboratories. There have been considerable benefits from adopting Coulter FACULTY for bone marrow reporting, including faster turnaround time, improved quality of the reports and cost savings.

Haematological validation of a computer-based bone marrow reporting system.

AIMS: To prove the safety and effectiveness of "Professor Belmonte", a knowledge-based system for bone marrow reporting, a formal evaluation of the reports generated by the system was performed. METHODS: Three haematologists (a consultant, a senior registrar, and a junior registrar), none of whom were involved in the development of the software, compared the unedited reports generated by Professor Belmonte with the original bone marrow reports in 785 unselected cases. Each haematologist independently graded the quality of Belmonte's reports using one of four categories: (a) better than the original report (more informative, containing useful information missing in the original report); (b) equivalent to the original report; (c) satisfactory, but missing information that should have been included; and (d) unsatisfactory. RESULTS: The consultant graded 64 reports as more informative than the original, 687 as equivalent to the original, 32 as satisfactory, and two as unsatisfactory. The senior registrar considered 29 reports to be better than the original, 739 to be equivalent to the original, 15 to be satisfactory, and two to be unsatisfactory. The junior registrar found that 88 reports were better than the original, 681 were equivalent to the original, 14 were satisfactory, and two were unsatisfactory. Each judge found two different reports to be unsatisfactory according to their criteria. All 785 reports generated by the computer system received at least two scores of satisfactory or better. CONCLUSIONS: In this representative study, Professor Belmonte generated bone marrow reports that proved to be as accurate as the original reports in a large university hospital. The haematology knowledge contained within the system, the reasoning process, and the function of the software are safe and effective for assisting haematologists in generating high quality bone marrow reports.

Differential diagnosis of L26-positive, CD15-negative Hodgkin's disease and large B-cell lymphoma with a high content of reactive T-cells: a morphologic and immunohistochemical study.

B-cell non-Hodgkin's lymphomas with a marked preponderance of reactive T cells, so-called T-cell rich B-cell lymphomas (TCRBCLs), can be morphologically confused with Hodgkin's disease (HD). To establish helpful distinguishing features in paraffin sections, 10 cases of L26-positive, CD15-negative HD and 10 cases of TCRBCL were compared; 4 cases of HD had morphologic features of the nodular lymphocyte predominant (LP) type. Nine of 10 cases of HD contained fewer than 20 mitoses/20 high power fields (hpf) and only 1 had pericapsular involvement. In contrast, 9 of 10 TCRBCL had greater than 20 mitoses/20 hpf and 7 had perinodal infiltration. HDLP was easily distinguished from TCRBCL by the expanded dendritic meshworks outlining the L & H nodules and the high content of CD57-positive lymphocytes. The remaining 6 cases of non-LP L26-positive HD had a relatively distinctive immunostaining pattern, with absence of CD45 and discordant reactivity for L26 and Ki-B5 in Reed-Sternberg cells and variants. Only 3 cases of TCRBCL had a similar CD45 and L26/Ki-B5 immunostaining pattern, and these could be distinguished by demonstrable cytoplasmic light-chain restriction. These results show that evaluation of the mitotic count, pericapsular involvement, and immunohistochemical staining patterns for Ki-M4p, CD57, L26/Ki-B5, and CD45 can help to discriminate TCRBCL from L26-positive HD when only fixed material is available.

Multiparameter case studies using knowledge-based systems in hematology.

Knowledge-based systems in diagnostic medicine are often used for teaching medical decision making. We have extended the educational value of our suite of hematology decision support systems (peripheral blood analysis, flow cytometry immunophenotyping and DNA analysis, and bone marrow morphology) by creating case studies in a hypertext format. The case studies use the knowledge-based system screens as a background. Digitized images of blood and bone marrow smears from the teaching cases can be accessed on-line. The case studies, which are designed primarily for technologists and physicians, emphasize the proper multiparameter approach to hematopathology diagnosis.

Chronic lymphocytic leukemia with an interfollicular architecture: avoiding diagnostic confusion with monocytoid B-cell lymphoma.

Certain low grade B-cell lymphoproliferative disorders can be mistaken for each other morphologically, particularly when there is partial lymph node involvement. We encountered two cases of chronic lymphocytic leukemia, in which the interfollicular growth pattern and the pale appearance of the neoplastic proliferation in the lymph nodes led to a misclassification as monocytoid B-cell lymphoma. The correct diagnosis was established, however, when the lymph node morphology was carefully reexamined, with the knowledge of the clinical history, peripheral blood findings, and bone marrow data. The immunophenotype of the neoplastic cells in the peripheral blood (CD5, CD23, weak fluorescence intensity of surface immunoglobulin and CD22) and the lymph node immunohistochemistry (weak L26 staining, strong MT1 positivity) confirmed the diagnosis of chronic lymphocytic leukemia. These two cases demonstrate the necessity of a systematic approach to lymph node morphology and the utility of a multiparameter approach in the diagnosis of lymphoproliferative disorders.

Are normative expert systems appropriate for diagnostic pathology?

Conceptual models for diagnostic reasoning proposed in the medical literature are presented to stimulate discussion about the issue of the appropriateness of probabilistic knowledge-based systems for medical diagnosis. Evidence is presented to corroborate the authors' view that diagnosis is a problem-solving task, rather than a decision-making task. In the authors' opinion, probabilistic reasoning is better suited to situations dealing with choices for clinical intervention, rather than to those dealing with determining the correct diagnosis. A critique is given of a diagnostic Bayesian expert system for lymph node pathology. In empirical studies, diagnostic Bayesian systems have been shown to typically list the correct diagnosis as the program's first choice 60% to 70% of the time. One reason for this undistinguished level of diagnostic performance is that Bayesian systems are not designed to represent and use knowledge the same way that an expert does.

An automated hematology laboratory with computer-controlled robotics.

A highly automated hematology laboratory environment is described that has conveyance systems to move bar-coded specimens from one station ("workcell") to another, robotic handling devices to load and unload hematology analyzers, and a hematology workstation. Computer systems monitor the process and equipment, track the specimen, manage inventory, and interpret patient results. When a specimen arrives at the laboratory, the bar-code determines which workcell the specimen should go to for testing. Each specimen is handled individually and in real-time. Hematology specimens are routed to a workcell of Coulter STKS analyzers where complete blood counts with five-part leukocyte differentials are performed under full robotic control. The entire process is managed by a real-time Windows-based process control system that interacts with a networked laboratory information system. The hematology workstation is being evaluated for interpretive results reporting and to determine follow-up testing.

A diagnostic workstation for neoplastic bone marrow diseases: evaluation on 526 cases.

The diagnostic accuracy of a workstation for neoplastic bone marrow pathology was evaluated on 526 cases from two institutions. The workstation consists of knowledge-based systems for peripheral blood analysis, flow cytometry immunophenotyping, and bone marrow morphology, linked together by a relational database. The "gold standard" diagnosis was established by complete agreement among three hematopathologists after independent review of the data from each case. The workstation's diagnosis agreed with the "gold standard" in 515 cases (97.9%). In six of the 11 diagnostic errors, the bone marrow module could not reach a final diagnosis. The five misclassifications would not have resulted in a change of therapy for the patient. The institutional diagnosis of record agreed with the gold standard in 462 cases (87.8%). The results indicate that the workstation is capable of high-quality, reproducible, multiparameter interpretive reporting.

Potential diagnostic pitfalls caused by blood film artifacts in prolymphocytic leukaemia. Observations in two cases.

The diagnosis of lymphoproliferative disorders is based on a combined evaluation of the clinical, immunological and morphological findings. Cytological details may vary with the quality of the smear. We report two cases of prolymphocytic leukaemia in which cytoplasmic hairs or protrusions were observed when the films were not dried quickly. In one case the artifacts led to an initial erroneous interpretation of hairy cell leukaemia 'variant'. The cytoplasmic outline was smooth in both cases when the smears were immediately fan-dried. The findings underscore the necessity of high standards of excellence, even for the simple technique of blood film preparation, in order to avoid undesirable artifacts which may result in diagnostic misinterpretation.

A knowledge-based system for the interpretation of flow cytometry data in leukemias and lymphomas.

Flow cytometry immunophenotyping and analysis of DNA ploidy and proliferative activity have become extremely helpful techniques for diagnosing and subclassifying hematopoietic cell populations in a modern, full-service hematopathology laboratory. The number of physicians with special training in the interpretation of these studies is limited. A knowledge-based computer system has been designed to aid in the interpretation of immunophenotyping and DNA flow cytometry results in hematopoietic disease. The system, known as "Professor Fidelio," is a heuristic classification system that reasons on the basis of defined diagnostic patterns. In this study, Fidelio was tested as a stand-alone system on 366 specimens from two large tertiary medical centers. Fidelio's interpretation was considered to be appropriate in all cases. In 300 of 366 (82%) specimens, the system's interpretation agreed with the diagnosis of record. Many of the disagreements could be traced to errors in the recording of the original diagnosis and minor differences in diagnostic criteria between Fidelio's knowledge base and the criteria in use at the medical centers. When used in a stand-alone mode, Fidelio's interpretation was less specific than the diagnosis of record in certain lymphoproliferative disorders that require morphologic information for subclassification. Professor Fidelio is one module in a workstation for the diagnostic hematology laboratory. This workstation is designed for interpretive reporting, education, and database functions for clinical research. Clinical and morphologic information are shared between Fidelio and the other modules for peripheral blood analysis, bone marrow morphology, and lymph node interpretation by means of a relational database. The system will be useful in hospitals that lack individuals specially trained in flow cytometry.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiparameter interpretative reporting in diagnostic laboratory hematology.

Accurate diagnosis and classification of hematologic malignancies (acute leukemias and chronic lymphoproliferative disorders) requires a multiparameter approach including peripheral blood analysis, bone marrow examination, and immunophenotyping. We have designed knowledge-based computer systems for interpretation of the hemogram and peripheral blood smears, analysis of flow cytometric immunophenotyping panels, and morphologic assessment of bone marrow specimens. The 3 modules share a relational database which includes pertinent clinical history in addition to the laboratory results. The bone marrow module automatically writes a complete interpretative report with a final diagnosis by searching all of the databases for appropriate clinical, peripheral blood, and immunophenotyping information. The ability of the 3 modules to interact, and the quality of the interpretative reports were tested on 100 consecutive patients with leukemia. The final diagnosis made by the bone marrow system agreed with the hospital diagnosis in 94 cases and the authors' interpretation in 99 of 100 cases.

An unusual pattern of lymph node involvement in mycosis fungoides simulating neoplastic follicles.

We describe an unusual pattern of lymph node involvement in a case of mycosis fungoides. The neoplastic proliferation formed pale nodules composed of small, irregular lymphoid cells, features that, on routine paraffin sections, suggested neoplastic follicles and a B-cell phenotype. The correct diagnosis was established by immunohistochemical studies that demonstrated a T-cell phenotype. Polymerase chain reaction for rearrangement of the T-cell receptor gamma gene confirmed that the proliferation was monoclonal. This case demonstrates that both architectural pattern and cytologic features may be unreliable in predicting immunologic phenotype. Immunologic marker studies and careful attention to the clinical history are vital to classify lymphoproliferative disorders correctly.

Castleman's disease. Differences in follicular dendritic network in the hyaline vascular and plasma cell variants.

Twenty-seven cases of the hyaline vascular variant and 10 cases of the plasma cell variant of Castleman's disease were studied with the paraffin resistant monoclonal antibodies Ki-FDC1p and/or Ki-M4p against follicular dendritic cells. Studies with the monoclonal antibody Ki-M9, for the detection of sinus lining cells, were also performed on the available frozen tissue in four cases of the hyaline vascular variant. In nine of the 10 plasma cell variant cases, the predominant type of follicular dendritic cell network was similar to that seen in normal or reactive germinal centres. In contrast, the hyaline vascular variant demonstrated either an expanded, disrupted, follicular dendritic cell network (10 cases) or multiple tight collections of follicular dendritic cells (16 cases). Sinus lining cells were not detected in the four cases studied. The difference in the predominant type of dendritic meshwork is an additional distinguishing feature to separate the plasma cell and hyaline vascular variants of Castleman's disease. The patterns of dendritic network seen in the hyaline vascular type, together with the absence of sinus lining cells, appear to favour the hamartoma theory proposed for this variant.

An expert system for the interpretation of flow cytometric immunophenotyping data.

The development of high-grade non-Hodgkin's lymphomas in HIV-positive patients and patients with acquired immune deficiency syndrome (AIDS) is a well known phenomenon. The proper classification of these neoplasms often requires a multiparameter approach, including the interpretation of a large panel of immunologic markers analyzed by flow cytometry. The availability of individuals with the required expertise to properly interpret these marker studies is limited. For this reason, we have designed an expert system to automate the analysis of immunophenotyping panels in both HIV-related and non-HIV-related hematopoietic neoplasms. The expert system, which we call "Professor Fidelio", runs on IBM-compatible computers under Windows 3.0. The system is designed to accept any number of markers studied from a repertoire of 35 markers. Professor Fidelio functions on the basis of heuristic classification of defined diagnostic patterns. Nine specific patterns (Stem Cell, Myeloid and/or Monocytic, Erythroid, Megakaryocytic, Immature B-cell, Immature T-cell, Mature B-cell, Mature T-cell, and Plasma cell) and one "non-specific" pattern have been agreed upon. Fidelio's knowledge base contains the definitions of each of these patterns and the heuristics for excluding patterns when an incomplete panel of markers is performed. The inference engine interprets the findings (including the age of the patient) and reports the patterns which are matched, the differential diagnosis, the suggested diagnosis from the list of differentials if the marker studies are specific, and recommendations for additional tests which may be valuable in establishing the diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymph node classification systems in cutaneous T-cell lymphoma. Evidence for the utility of the Working Formulation of Non-Hodgkin's Lymphomas for Clinical Usage.

BACKGROUND: This study was undertaken to compare three classification schemes used to evaluate lymph nodes (LN) obtained from patients with cutaneous T-cell lymphoma (CTCL): a modified Rappaport classification, the National Cancer Institute-Veterans Administration (NCI-VA) classification based on the relative numbers of cerebriform cells in the paracortical areas, and the Dutch classification based on the presence of cerebriform cells with large nuclei in mycosis fungoides (MF) and diffuse infiltration by cerebriform cells in Sézary syndrome. METHODS: A study set of 195 LN obtained from patients with CTCL (MF, Sézary syndrome, and nonepidermotropic T-cell lymphomas) and 14 LN from patients with benign dermatoses was reviewed independently by three groups of pathologists familiar with each classification system. RESULTS: Each classification system provided useful prognostic information. However, contrary to prior reports, no significant difference in survival was apparent in patients with uneffaced LN when classified according to the NCI-VA (LN0-2 versus LN3) or Dutch (Gr0-1 versus Gr2) ratings. In addition, all classification systems demonstrated a poor survival time associated with effaced LN. By combining results from the modified Rappaport and Dutch classifications, three prognostic groups could be identified based on cell morphology: a low-grade category with a small cell histologic subtype (median survival time, 40 months); a high-grade immunoblastic subtype (median survival time, 9 months) composed of cells with an oval nucleus containing a large, usually solitary central nucleolus; and an intermediate-grade category composed of all cases without the distinctive small cell and immunoblastic morphologies (median survival time, 26 months). CONCLUSIONS: The authors propose that clearly involved LN in CTCL can be categorized on the basis of cell morphology into prognostic groups analogous to what has been proposed for the Working Formulation for Non-Hodgkin's Lymphomas for Clinical Usage.

A clinical database as a component of a diagnostic hematology workstation.

A clinical database was designed as part of a comprehensive workstation for diagnostic laboratory hematology. The database stores coded findings pertinent to hematologic disorders including inherited abnormalities, previous surgery, malignancies, current therapy, and laboratory test results. The workstation includes knowledge-based systems for peripheral blood analysis, flow cytometry studies, and bone marrow morphology. The peripheral blood system renders an interpretive report based on data from a complete blood count with manual review of a blood smear by a technologist. The flow cytometry module interprets the immunophenotyping and DNA content results, and correlates them with the clinical findings and the peripheral blood data. The bone marrow system bases its report on all of the available information including the morphologic review of the bone marrow specimen by a physician, the peripheral blood data, immunophenotype, and clinical/laboratory findings. Before generating an interpretive report, each of the knowledge-based systems automatically searches the clinical database for specific information pertinent to the findings in the case. Since the workstation must function in situations where access to distributed databases is not feasible or not yet practical, a data entry module with a graphical user interface has been created.

Expert system design in hematology diagnosis.

A two-part study was designed to test the hypothesis that sufficient information is available from a modern hematology analyzer (the Coulter STKS) to reach a reliable intermediate conclusion which can be used as input to the next decision-making level in the design of a high-performance expert system for hematology diagnosis. In phase one, we analyzed the performance of three probabilistic systems (using Bayes' rule) which interpret STKS data: a control system which took the traditional approach of classifying cases into specific diagnoses, and two test systems which were designed to reach only an intermediate conclusion but not a final diagnosis. One of the test systems classified cases into "textbook categories" of disease and the other utilized defined diagnostic patterns. The systems were tested with 150 cases. The pattern approach ranked the correct choice first in 141 of 150 cases (94%). In phase two, we abandoned Bayes' rule, reformulated the pattern approach into a heuristic classification system, and tested its reliability on 820 cases. The algorithm of the reformulated system was able to classify all 820 cases into the same predominant pattern as a panel of three experienced laboratory hematologists.