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Multiple frequency bioelectrical impedance analysis (MFBIA) has previously been shown to provide accurate relative measures of lymphedema in the upper limb of patients (1). This paper reports the results of a three year prospective study to evaluate the efficacy of MFBIA to predict the early onset of lymphedema in patients following treatment for breast cancer. Bioelectrical impedance measurements and circumferential measurements of each upper limb were recorded in healthy control subjects (n = 60) to determine the normal range of the ratio (dominant/non-dominant) of extracellular and total limb volumes respectively. Patients undergoing surgery for the treatment of breast cancer were recruited as the study group; MFBIA and circumferential measurements were recorded pre-surgery, one month post-surgery and then at two month intervals for 24 months. One hundred and two patients were recruited into the study. Twenty patients developed lymphedema in the 24 months follow up period of this study. In each of these 20 cases MFBIA predicted the onset of the condition up to 10 months before the condition could be clinically diagnosed. Estimates of the sensitivity and specificity were both approximately 100%. At the time of detection by MFBIA, only one of the patients returned a positive test result from the total limb volumes determined from the circumferential measures. These results confirmed the suitability of the MFBIA technique as a reliable diagnostic procedure for the early detection of lymphedema.

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Lymphedema is an accumulation of lymph fluid in the limb resulting from an insufficiency of the lymphatic system. It is commonly associated with surgical or radiotherapy treatment for breast cancer. As with many progressively debilitating disorders, the effectiveness of treatment is significantly improved by earlier intervention. Multiple frequency bioelectrical impedance analysis (MFBIA) previously was shown to provide accurate relative measures of lymphedema in the upper limb in patients after treatment for breast cancer. This presentation reports progress to date on a three-year prospective study to evaluate the efficacy of MFBIA to predict the early onset of lymphedema in breast cancer patients following treatment. Bioelectrical impedance measurements of each upper limb were recorded in a group of healthy control subjects (n = 50) to determine the ratio of extracellular limb-fluid volumes. From this population, the expected normal range of asymmetry (99.7% confidence) between the limbs was determined. Patients undergoing surgery to treat breast cancer were recruited into the study, and MFBIA measurements were recorded presurgery, at one month and three months after surgery, and then at two-month intervals for up to 24 months postsurgery. When patients had an MFBIA measure outside the 99.7% range of the control group, they were referred to their physician for clinical assessment. Results to date: Over 100 patients were recruited into the study over the past two years; at present, 19 have developed lymphedema and, of these, 12 are receiving treatment. In each of these 19 cases, MFBIA predicted the onset of the condition up to four months before it could be clinically diagnosed. The false-negative rate currently is zero. The study will continue to monitor patients over the remaining year to accurately ascertain estimates of specificity and sensitivity of the procedure.

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PURPOSE: To assess changes in hepatic perfusion in patients with colorectal cancer with computed tomography (CT), diagnostic potential of CT perfusion measurements, and implications for design of contrast enhancement protocols. MATERIALS AND METHODS: In 27 patients with colorectal cancer, arterial and portal perfusion were calculated from temporal changes in attenuation after intravenous administration of contrast material. RESULTS: Arterial perfusion greater than 0.25 mL/min/mL was seen in nine (82%) of the 11 patients with overt metastases versus six (38%) of the 16 patients with no overt metastases (P < .05). Portal perfusion of 0.25 mL/min/mL or less was found in five (46%) of the patients with overt metastases versus three (19%) of the patients with no overt metastases. Follow-up imaging showed progressive metastatic disease in three patients, all of whom had decreased portal perfusion. CONCLUSION: Increased arterial perfusion appears to be an indicator of liver metastases, whereas reduced portal perfusion may indicate progressive disease. Contrast enhancement protocols that are based on experience with normal livers may not be optimal for patients with metastases.

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The treatment of lymphoedema includes a combination of massage, compression bandaging, and exercise. To date the most common technique of assessing the efficacy of treatment has involved estimating the total limb volume from circumferential measurements at fixed intervals along the limb. This study investigated the application of multiple frequency bioelectrical impedance analysis, MFBIA, to monitor the volume of lymphoedema in the upper limb of patients who developed this disorder following surgery for cancer of the breast. Daily measurements of both circumference and impedance of both the affected and unaffected limbs were recorded for 20 patients throughout their 4 week treatment programmes. Twenty control subjects were also monitored daily over a similar 4 week period. Prior to the commencement of treatment the bioimpedance technique detected a significant (P < 0.01) asymmetry between the two limbs of the control subjects, associated with handedness (P < 0.001). Circumferential estimates of limb volumes in the control group detected no asymmetry. Impedance measures of extracellular fluid showed all of the patients to lie outside the 95% confidence interval determined from the data of the control group. The trends of the impedance measures and the circumferential estimates of volume throughout the 4 week program were found to be significantly different (P < 0.05); MFBIA exhibiting a greater sensitivity in the detection of lymphoedema. The results demonstrate that MFBIA is significantly more sensitive than circumferential measurement both in the early diagnosis of lymphoedema and in monitoring change.

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The effect of a comprehensive lymphedema management program was assessed in 25 patients in whom moderate to severe lymphedema had developed after surgery and/or radiotherapy for carcinoma of the breast. Intensive treatment (4 weeks) involved massage, compression bandaging, and sequential pneumatic compression, with an adjunct program of education to provide skills in exercise, massage, bandage, and containment garment use. The intensive treatment phase was followed by a self-management phase based on the skills that had been acquired. A significant reduction in limb circumference and volume, with continuing improvement over 12 months of self-management, was observed. There was a decrease in need for physical assistance. Quality of life generally remained high and stable throughout the 12 months. Quality of life specific to lymphedema, however, declined during the intensive phase of treatment, but recovered and surpassed pretreatment levels during the self-management phase of treatment. Perceived comfort and strength in the lymphedematous limb improved, and perceived size decreased. The study confirmed that the combination of multimodal physical therapy and education for self-management reduces lymphedema and its adverse subjective consequences and maintains the improvement thus achieved.

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Alpha-interferon (alpha-IFN) therapy is an effective agent in early chronic phase (ECP) chronic myeloid leukemia (CML), achieving hematologic control in the majority and major cytogenetic response (MCR) (reduction in Ph' +ve metaphases to < 35%) in a substantial minority. Currently no pretreatment markers exist to ascertain likelihood of meaningful response. The site of breakpoint in M-bcr and relationship to prognosis is controversial. Studies have been hampered by variation in definition of breakpoint and difference in treatment protocols. In this study of ECP CML patients, Southern analysis and reverse transcription polymerase chain reaction (RT-PCR) were used to determine breakpoint location. Patients received alpha-IFN (9 x 10(6) units/day) and dose-adjusted hydroxyurea (HU) to maintain granulocyte count between 1.0-2.0 x 10(9)/l for 6 months or more. Twelve of 31 patients entered on the study achieved a MCR. The Sokal index did not predict for cytogenetic response to alpha-IFN. Eight of 11 patients with 5' breakpoint achieved MCR compared to only four of 20 patients with 3' breakpoint (P = 0.007). These results suggest site of M-bcr rearrangement may be predictive of response to alpha-IFN therapy. If verified by further study, this may allow more appropriate use of alpha-IFN with respect to other modalities such as allogeneic transplant.

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OBJECTIVE: To evaluate multimodal treatment (massage, pneumatic compression, bandaging and education) of post-mastectomy lymphoedema and to review methods of measurement of lymphoedema. DESIGN: Prospective cohort study with 12 months' follow-up. PATIENTS: Twenty-five consecutive women referred for lymphoedema examination after mastectomy to a private day-patient clinic attached to a tertiary referral hospital. INTERVENTION: Patients received multimodal therapy, including education on self-management techniques, for four weeks. MAIN OUTCOME MEASURES: Changes in body weight, limb circumference and volume, and patient reports of self-management (exercise, massage, bandaging and sleeve wearing). RESULTS: Excess limb volume decreased by approximately 40% immediately after treatment and by over 50% at 6 months' follow-up, remaining stable to 12 months' follow-up. Self-management that required assistance (massage and bandage wearing) declined more after treatment than did exercise or compression sleeve wearing. Correlations between body mass and limb volume and self-management and limb volume reduction were non-significant. CONCLUSION: Multimodal therapy reduced lymphoedematous limb volume by at least half in 18 of 25 patients. Patients can maintain these reductions independently through exercise and sleeve wearing and without further treatment. We used a replicable method of measuring lymphoedema, which we recommend for adoption by researchers in this field.

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The value of multiple frequency bioelectric impedence analysis (MFBIA) in the monitoring and management of post-mastectomy lymphoedema of the arm was evaluated in 15 patients and controls. The technique was found to produce quantitative agreement with a clinical diagnosis of lymphoedema and with the currently-used measure (limb volume calculated from circumferential measurements) of limb size. The significance of this finding lies in MFBIA being diagnostically informative: it indicates when an observed change in limb volume is directly, albeit theoretically, attributable to accumulation of extracellular fluid. MFBIA potentially offers the means for earlier definitive diagnosis and more-accurate monitoring of extracellular fluid changes during and after treatment.

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Plasma concentrations of cross linked fibrin degradation products, a marker of intravascular thrombosis and fibrinolysis, were measured in 495 patients with suspected pulmonary embolism referred for ventilation-perfusion lung scanning to determine whether concentrations are increased in pulmonary embolism and their potential use in diagnosis. Lung scans were described as normal (n = 66) or as showing a low (n = 292), indeterminate (n = 58), or high probability (n = 79) of pulmonary embolism. There was a difference between the mean levels of cross linked fibrin degradation products in each scan category: normal scans, 142 ng/ml; low probability scans, 295 ng/ml; indeterminate probability scans, 510 ng/ml; high probability scans, 952 ng/ml (p less than 0.001). Of the patients with high probability scans, 96% had raised concentrations. Explanations for discrepant low results include incorrect scan diagnosis, delay in blood sampling, and anticoagulation. Of the patients with a low or indeterminate probability of pulmonary embolism, 43% had increased concentrations of cross linked fibrin degradation products that could be attributed in most cases to another illness. Owing to the wide range of values in each lung scan diagnostic category, raised concentrations of these fibrin degradation products cannot be used without reference to the patient's clinical state as a discriminatory test for pulmonary embolism. Further evaluation of the significance of normal concentrations in excluding a diagnosis of pulmonary embolism appears to be warranted.

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Collagenase digestion allows cells to be released into suspension from bone marrow tissue. Discrete abnormal populations of lymphoid cells can be identified by cell morphology and immunological phenotyping techniques. Viable cells are also available for chromosomal analysis. This technique makes cells available for analysis in cases of dry bone marrow taps and has a particular use in the investigation of bone marrow involvement by malignant lymphoma.

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A technique for the extraction of cells from bone marrow trephine core biopsy specimens using collagenase digestion was assessed in 39 cases (33 diagnostic and six normal). Diagnostically useful numbers of cells were extracted from all marrows. Morphological assessment of cytocentrifuge preparations of these cells gave a correct diagnosis in 23 (60%) of cases compared with 27 (70%) for the corresponding aspirated marrow smears. Phenotypic analysis using flow cytometry showed persistence of a range of surface membrane antigens following collagenase digestion. Increased autofluorescence was a problem in some cases. Cytochemistry, bone marrow culture, and cytogenetic analysis could also be carried out on these cells. It is concluded that this technique has useful diagnostic applications in cases of dry taps.

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The results are reported of a clinical and laboratory evaluation of the use of a random-access centrifugal analyzer linked to a personal computer in the management of the routine workload of a hemostasis laboratory. Over a three-month period, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin clotting time (TCT), and derived fibrinogen (Fib) were performed on a total of 929 samples. Included in the study were 448 samples from patients receiving anticoagulants (oral anticoagulants, 228; heparin, 166; heparin and warfarin, 130) and 351 samples from patients requiring coagulation screens (PT, APTT, TCT, Fib). Tests were done in parallel with tilt-tube manual techniques and the results correlated. The correlation coefficients were PT, 0.99; TCT, 0.72; APTT, 0.96; Fib, 0.97. Discrepancies were analyzed and were due to hypofibrinogenemia and hyperlipidemia. The poorer correlation coefficient of TCT was attributable both to lower reproducibility of the manual test and the effect of dysfibrinogenemia or FDPs in liver disease. In no case was an abnormality or diagnosis missed using the centrifugal analyzer. In several cases the increased sensitivity of the analyzer improved the detection of the lupus anticoagulant. The use of automation was accompanied by a major reduction in workload and reagent costs. The machine has been used to assay a wide range of coagulation tests by clot based and chromogenic substrate methods. In conclusion, a programmed centrifugal analyzer is a safe, efficient, and flexible way of automating routine coagulation tests. It widens the reportoire of tests performed in the Hemostasis laboratory by using a machine capable of being used in other areas of pathology.

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The measurement of crosslinked fibrin derivatives in plasma has received evaluation as a screening test in the diagnosis of venous thrombosis. Plasma samples were taken from 104 patients undergoing venography because of clinical suspicion of lower limb venous thrombosis. The samples were assayed using a monoclonal antibody identifying an epitope on D dimer and larger crosslinked fibrin derivatives in an enzyme immunoassay. 100% of patients with positive venograms had elevated levels of these molecules. While a percentage of patients with negative venograms also had increased levels, alternative clinical explanations were apparent in most. A normal D dimer value excludes the diagnosis of venous thrombosis, while an increased value supports it. The measurement of crosslinked fibrin derivatives in plasma may play a role in the selection of patients for venography.

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In a random cross-over design, six healthy consenting adult volunteers were given on separate occasions single doses of 300-650 mg of 3 different formulations of enteric-coated aspirin. Over various intervals for 48-54 h following dosage, plasma aspirin and salicylate concentrations were measured together with percentage inhibition of platelet aggregation activated by threshold concentrations of sodium arachidonate alone and combined with ADP and collagen. In all subjects each formulation delivered measurable quantities of aspirin to the peripheral circulation, the unchanged drug being detected at various times up to and including 28 h after dosage. Moreover, low aspirin concentrations were found to co-exist with unimpaired platelet aggregation. All 3 formulations yielded statistically significant (P less than 0.01) inhibition of platelet aggregation activated both by arachidonate and by the combination of aggregants when tested 24-29 and 48-54 h after dosage; there were no significant differences (P greater than 0.05) between the 3 formulations in this regard. Two different patterns of delivery of unchanged aspirin to the systemic circulation from these enteric-coated formulations were apparent. These patterns may be important when considering which aspirin formulation might be most appropriate in chronic use for an antiplatelet effect. None of the enteric-coated formulations used in this study may be optimal in this regard.

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Conformational and structural changes on conversion of fibrinogen to fibrin and its cross-linking by Factor XIIIa lead to the development of new antigenic determinants that permit differentiation between their plasminolytic cleavage products. A monoclonal antibody (DD-3B6/22) that is specific for cross-linked fibrin derivatives containing the D dimer configuration has been used in developing a latex agglutination procedure that can detect fibrin degradation products in either plasma or serum. Fibrinogen or its degradation products do not cross-react with this antibody. Results were calibrated with an enzyme immunoassay, which used a purified D dimer standard. Plasmas from 40 normal subjects, all having D dimer levels below 250 ng/mL measured by enzyme immunoassay, were all negative by latex assay. In contrast, positive latex agglutination titers were obtained with 87 of 88 patients with demonstrated deep venous thrombosis, pulmonary embolism, or disseminated intravascular coagulation. Compared to enzyme immunoassay, latex agglutination assay is less sensitive, but this latex procedure provides a rapid and less elaborate test for elevated levels of cross-linked fibrin degradation products in patients with thrombosis. Plasma assays for fibrin degradation products are preferable to those using serum.

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An instance of cerebral abscess presenting with episodes of palinopsia occurred in a patient suffering from acute myelogenous leukaemia. Palinopsia is a very uncommon symptom in cerebral disease. Review of hospital autopsy records for a decade revealed 280 other instances of haematological malignancy, in only one of which a cerebral abscess was also present.

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Fibrinogen degradation, fibrin polymerisation, and the insertion of cross links into fibrin by fibrin stabilising factor lead to the appearance of new antigenic determinants. Antibodies against these antigenic sites may react specifically with the derivatives but not with the parent molecules. We have utilised a monoclonal antibody, which interacts with the cross linked fragment D dimer and related high molecular weight fibrin derivatives, to develop an enzyme immunoassay which measures cross linked fibrin derivatives in plasma and serum using D dimer as standard. Mean concentration in plasma from normal subjects was 75 ng/ml with an upper limit of about 144 ng/ml. Concentrations in patients with pulmonary embolism, deep venous thrombosis, arterial thromboembolism, and disseminated intravascular coagulation were raised in all cases. Confirmation of the specific increase of cross linked fibrin derivatives in patients with disseminated intravascular coagulation was obtained by parallel monitoring of their fibrin degradation products in serum using affinity chromatography and sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis. In many patients the plasma concentrations greatly exceeded the serum values of cross linked fibrin degradation products, suggesting that the procedure can measure fibrin derivatives in plasma which are absent from serum.

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We have prepared a monoclonal antibody which recognises an antigenic determinant on D dimer, a specific fragment resulting from the degradation of crosslinked fibrin. This antibody has been used in the development of an enzyme-linked immunoassay for D dimer and related degradation products containing crosslinked gamma-gamma chains, to provide a simple assay of circulating crosslinked fibrin degradation products suitable for clinical use. Since these crosslinked fibrin degradation products are characteristic of fibrinolysis, as distinct from fibrinogenolysis, their measurement should aid in the diagnosis, evaluation and monitoring of thrombotic and thrombolytic states. In preliminary studies, low concentrations of crosslinked fibrin derivatives were detected in normal sera. High levels were found in 30/30 patients with disseminated intravascular coagulation and in the majority of patients having deep venous thrombosis or pulmonary embolism.

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