Early diagnosis of lymphedema using multiple frequency bioimpedance.

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.

Early diagnosis of lymphedema in postsurgery breast cancer patients.

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.

Long-term interferon-alpha 2A does not induce sustained hematologic remission in younger patients with essential thrombocythemia.

The ability of Interferon alpha (alpha-IFN) to alter the natural history of essential thrombocythemia (ET) and induce sustained hematologic remission would provide further impetus to consider this agent in younger patients with this disease and may influence the decision to commence treatment in asymptomatic patients. This study has failed to demonstrate any sustained hematologic remissions after cessation of long-term (2 years) alpha-IFN administration in a group of 34 female patients with a median age of 41 years (range 14-68) who were considered at intermediate to high risk of thrombotic complications. In the twenty-one patients completing two years of therapy, 13 (62%) had complete hematological responses (CHR; platelet count <400 x 10(9)/L), 7 (33%) partial hematological responses (PHR; platelet count 400-600 x 10(9)/L) and no thrombotic or hemorrhagic complications occurred. In all patients who discontinued alpha-IFN at 2 years, platelet counts rose above the normal range within 1-4 months and the majority required reinstitution of some form of therapy. The inability of long-term alpha-IFN to induce sustained, unmaintained hematologic remission argues strongly against any significant effect on the neoplastic clone at the doses used in this study. This study does, however, confirm the efficacy of long-term alpha-IFN in younger female patients with ET, a group not previously well represented in clinical trials of the agent.

CT measurement of perfusion and permeability within lymphoma masses and its ability to assess grade, activity, and chemotherapeutic response.

PURPOSE: Structural CT criteria such as nodal size and appearance have a poor correlation with the grade and activity of a lymphoma mass. This study investigates the potential for functional CT perfusion and permeability measurements to assess lymphoma grade and activity. METHOD: Thirty-nine patients with proven lymphoma underwent 47 dynamic contrast-enhanced CT studies. Lymphoma grade was classified as low or intermediate/high. In seven patients who underwent repeated studies, measurements were correlated against change in disease activity in the intervening period. RESULTS: Median perfusion values were higher in active disease (0.55 vs. 0.37 ml/min/ml) and intermediate/high-grade lymphoma (0.56 vs. 0.46 ml/min/ml). Perfusion below 0.2 ml/min/ml implied inactive disease (p < 0.03), whereas > 0.5 ml/min/ml suggested intermediate/high-grade lymphoma (p = 0.11). Median values of permeability were little different between patient groups. Only perfusion fell when disease became inactive. CONCLUSION: Only CT perfusion measurements of nodes have potential for assessing lymphoma grade, activity, and treatment response.

Efficacy, safety and tolerability of anagrelide in the treatment of essential thrombocythaemia.

BACKGROUND: Essential thrombocythaemia (ET) has an associated risk of thrombotic and haemorrhagic complications, which can be minimised by control of the platelet count. Anagrelide selectively lowers the platelet count, however, there is little Australasian experience with its use and scant data on symptom control. AIMS: To evaluate the efficacy of anagrelide for platelet reduction and symptom control in a broad cohort of patients with well-defined ET, and to determine the safety and tolerability in such a population. METHODS: Seventeen patients with ET and a platelet count > 600 x 10(9)/L were prospectively enrolled. The evaluable four males and 12 females with a median age of 58 years (range 14-79) included ten patients (63%) previously treated with two or more agents and 12 patients (75%) who had failed other therapies. The median follow-up was seven months (range 15 days to 36 months). RESULTS: Anagrelide, in an average dose of 1.9 mg/day, reduced the platelet count from a mean of 728 x 10(9)/L (95% CI 611-845 x 10(9)/L) to 412 x 10(9)/L (95% CI 319-504 x 10(9)/L) (p < 0.001) and maintained it at this level. Fourteen patients (88%) had a platelet reduction to < 600 x 10(9)/L. All symptomatic patients had improvement in symptoms attributable to thrombocythaemia. There were three haemorrhagic and three thrombotic episodes in a total of three patients (19%), including one death from an intracerebral haemorrhage. Six patients (37%) were removed from therapy due to toxicity after a median of 151 days. Side effects included palpitations, abdominal pain and cough. CONCLUSIONS: Anagrelide is efficacious and safe in ET, both for platelet and symptom control. Minor side effects are common, however, tend to occur early and resolve spontaneously in most cases.

Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte-colony stimulating factor.

Twenty-one patients with advanced chronic myeloid leukemia (late chronic phase (n = 8), accelerated phase (n = 11) and blast crisis (n = 2)) were treated with idarubicin, cytarabine, and etoposide followed by G-CSF and subsequent collection of peripheral blood progenitor cells in the early recovery phase. Treatment was reasonably well tolerated with no deaths or intensive care admissions. Despite the advanced phase of disease and heavy pretreatment with cytotoxics and interferon-alfa, 11 of 21 patients (52%) achieved a cytogenetic response. Of the nine major cytogenetic responses (complete (n = 3) and partial (n = 6)), seven achieved adequate progenitor collections for consideration for autologous transplantation. The only predictor of response was disease duration (P = 0.02). With a median follow-up of 1171 days from treatment it appears unlikely that G-CSF contributed to disease progression. Survival post-IcE was predicted by disease stage (P = 0.0001). Intensive chemotherapy followed by G-CSF allowed adequate yields of predominantly Philadelphia chromosome negative progenitor cells to be obtained from one-third of patients with advanced CML.

In vivo assessment of neovascularization of liver metastases using perfusion CT.

Neovascularization of tumours produces a high microvessel density. Although diagnostic imaging is unable to visualize microvessels directly, it is possible to demonstrate associated changes in tissue perfusion. The aim of this study was to use the quantitative functional information and high spatial resolution of perfusion computed tomography to study neovascularization of hepatic metastases. Perfusion CT was performed in 13 patients with hepatic metastases from various primary tumours. Arterial perfusion was measured in the metastasis; both arterial and portal perfusion were measured in a small rim of liver tissue immediately adjacent to the metastasis. Perfusion measurements were correlated against survival of the patient in nine cases. Arterial perfusion was increased above normal values, both in the metastasis (median: 0.62 ml min-1 ml-1; range: 0.26-3.05 ml min-1 ml-1) and in the adjacent liver (median: 0.51 ml min-1 ml-1; range: 0.14-1.60 ml min-1 ml-1). Portal perfusion of adjacent liver was highly variable (median: 0.30 ml min-1 ml-1; range: 0.05-1.85 ml min-1 ml-1). Arterial perfusion was positively correlated with portal perfusion within liver tissue adjacent to metastases (p < 0.05, r = 0.58), a reversal of the normal situation. Survival of the patient correlated with arterial perfusion within the metastasis (p < 0.05, r = 0.69) but more closely with arterial perfusion in the adjacent liver (p < 0.02, r = 0.78). In conclusion, alterations in perfusion within metastases and adjacent liver are in accordance with the histological features of neovascularization. Perfusion CT offers a method for studying neovascularization in the living patient and offers prognostic information.

Colorectal cancer: diagnostic potential of CT measurements of hepatic perfusion and implications for contrast enhancement protocols.

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.

High response rates with short infusional 2-chlorodeoxyadenosine in de novo and relapsed low-grade lymphoma. Australian and New Zealand Lymphoma Study Group.

Thirty-five patients (eight de novo, 27 relapsed disease) with low-grade non-Hodgkin's lymphoma (diffuse small lymphocytic, follicular small cleaved cell, follicular mixed cell, and lymphoplasmacytoid) were treated with 2-chlorodeoxyadenosine (2CdA) at a daily dose of 0.14 mg/kg for 5d (2 h infusion) for an average of three cycles. Minor treatment delays, generally due to haematological toxicities, occurred in nine of 105 cycles. Major toxicities were lymphopenia, neutropenia and thrombocytopenia. Opportunistic infections occurred in seven patients. Overall response rate was 69% (five complete, 19 partial) reaching 88% for de novo patients (two complete, five partial). Elevated beta 2-microglobulin level was negatively predictive of response (P = 0.0014). Eight of 24 responders relapsed, with a median follow-up of 13 months. 2CdA administered as an intermittent infusion shows considerable single-agent activity in low-grade lymphomas achieving high response rates of prolonged duration. Consideration of schedules where 2CdA is alternatively administered with combination chemotherapy appears warranted.

Bioelectrical impedance for monitoring the efficacy of lymphoedema treatment programmes.

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.

Psychosocial benefits of postmastectomy lymphedema therapy.

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.

Cytogenetic response to alpha-interferon is predicted in early chronic phase chronic myeloid leukemia by M-bcr breakpoint location.

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.

Post-mastectomy lymphoedema treatment and measurement.

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.

Multi-frequency bioelectrical impedance augments the diagnosis and management of lymphoedema in post-mastectomy patients.

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.

All-trans retinoic acid in the treatment of acute promyelocytic leukaemia.

All-trans-retinoic acid (ATRA) is known to induce differentiation of promyelocytes in vitro and also to induce remission of acute promyelocytic leukaemia in vivo. We treated 11 patients with poor prognosis acute promyelocytic leukaemia (APL) with ATRA and obtained seven complete and one partial remission. Remissions took one to three months to achieve and were associated with adverse effects including dry skin and bone pain. In eight patients the white cell count rose above 20 x 10(9)/L within the first ten days of retinoic acid treatment and this was associated with the development of pulmonary leukostasis in three patients which was fatal in one. Another two patients died of intracranial haemorrhage also within the first ten days. ATRA is a promising new agent in the induction therapy of this particular category of acute leukaemia.

Plasma cross linked fibrin degradation products in pulmonary embolism.

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.

Cell Suspensions from Collagenase Digestion of Bone Marrow Trephine Biopsy Specimens-its Use in Lymphoma.

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.

Cell suspensions from collagenase digestion of bone marrow trephine biopsy specimens.

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.

Automation of routine coagulation testing using a random access centrifugal analyzer.

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.