Biocompatible, high precision, wideband, improved Howland current source with lead-lag compensation.

The Howland current pump is a popular bioelectrical circuit, useful for delivering precise electrical currents. In applications requiring high precision delivery of alternating current to biological loads, the output impedance of the Howland is a critical figure of merit that limits the precision of the delivered current when the load changes. We explain the minimum operational amplifier requirements to meet a target precision over a wide bandwidth. We also discuss effective compensation strategies for achieving stability without sacrificing high frequency output impedance. A current source suitable for Electrical Impedance Tomography (EIT) was simulated using a SPICE model, and built to verify stable operation. This current source design had stable output impedance of 3.3 MΩ up to 200 kHz, which provides 80 dB precision for our EIT application. We conclude by noting the difficulty in measuring the output impedance, and advise verifying the plausibility of measurements against theoretical limitations.

Pre-mobilization therapy blood CD34+ cell count predicts the likelihood of successful hematopoietic stem cell mobilization.

We examined pre-mobilization blood CD34+ cell count to predict ability to mobilize adequate peripheral blood progenitor cells (PBPC) in 106 cancer patients and 36 allogeneic donors. Mean pre-mobilization therapy blood CD34+ cell count was 3.1 cells x 10(6)/l (s.d. = 3.9, r = 0.3-37) and mean CD34+ cells collected were 5.3 x 10(6) cells/kg/leukapheresis procedure (s.d. = 7.0, r = 0.03-53). Yields correlated with pre-mobilization CD34+ cells x 10(6)/l (r = 0.37, P-value < 0.0001); correlation was stronger in allogeneic donors (r = 0.56, P-value = 0.0004) and males (r = 0.46, P-value < 0.0001). Based on classification and regression tree multivariate analysis, the predictive value of pre-mobilization blood CD34+ cell count was confounded by other variables, including age, gender, mobilization regimen and malignancy type. We generated an algorithm to predict a minimum PBPC yield of 1 x 10(6) CD34+ cells/kg/leukapheresis procedure after mobilization. A threshold pre-mobilization blood CD34+ cell count of 2.65 cells x 10(6)/l was the most important decision point in predicting successful mobilization. Only 2% of subjects with pre-mobilization blood CD34+ cell counts > 2.65 cells x 10(6)/l did not achieve the minimum per apheresis, whereas 24% with pre-mobilization values below threshold had inadequate mobilization. Prospectively identifying individuals at risk for mobilization failure would allow for improved treatment planning, resource utilization and time saving.

Increasing underrepresentation of elderly patients with advanced colorectal or non-small-cell lung cancer in chemotherapy trials.

BACKGROUND: Elderly patients are underrepresented in chemotherapy trials for advanced colorectal cancer (CRC) and non-small-cell lung cancer (NSCLC). However, the change in underrepresentation over time has not been documented. AIMS: This study aimed to quantify (i) the change in the median age of patients enrolled in clinical trials for metastatic CRC and NSCLC between 1982-1991 and 1992-2001 compared with the general colorectal and lung cancer population, and (ii) the proportion of trials with an upper age limit for eligibility. METHODS: A retrospective review of data from the Victorian Cancer Registry and all large published randomized chemotherapy trials for advanced CRC and NSCLC between 1982 and 2001 was conducted. RESULTS: The median age of patients with CRC enrolled in clinical trials remained constant between the two decades (62.0 and 62.2 years), whereas the median age of the CRC population increased from 68.4 to 70.2 years, increasing the median age difference from 6.4 to 8.0 years. The median age of patients with lung cancer in clinical trials increased from 59.8 to 61.8 years, whereas the median age of the lung cancer population increased from 67.4 to 70.4 years, widening the age difference from 7.6 to 8.6 years. More trials set an upper age limit for eligibility in the first decade than in the second decade for both CRC (51 vs 29%, P = 0.04) and NSCLC (68 vs 41%, P = 0.03). CONCLUSION: International clinical trials for CRC and NSCLC are becoming increasingly unsuitable for application to Australian patients because of the increasing age discrepancy, despite fewer trials restricting eligibility by age.

Five years managing metastatic non-small cell lung cancer: experience at a teaching hospital.

BACKGROUND: The management of patients with metastatic non-small cell lung cancer (NSCLC) is complex. Some studies have demonstrated that the care of patients with NSCLC may be suboptimal. AIM: To review the management of patients with metastatic NSCLC treated at a single teaching hospital over a 5-year period. METHOD: All patients with metastatic NSCLC treated at a single teaching hospital over a 5-year period (1998-2002) were identified. Data were collected by a retrospective record review. RESULTS: Of 343 patients with metastatic NSCLC, 157 patients were deemed eligible for this review. Thirty-one patients (19%) were admitted to the Medical Oncology Unit at initial presentation. Twenty-four patients (15%) were not referred to either the Medical Oncology Unit or the Palliative Care Unit. Forty-four patients (28%) received chemotherapy, six of whom (14%) were enrolled onto a clinical trial. Six separate chemotherapy regimens were used. The median survival was 5 months and the 1-year survival rate was 19.8%. CONCLUSIONS: The present audit demonstrates some shortfalls in the optimal clinical care of patients with metastatic NSCLC at a large teaching hospital. The main selection criteria of consideration for chemotherapy are age, performance status and presence of symptoms. A subset of patients was not referred to either the Medical Oncology Unit or the Palliative Care Unit and consistency in the choice of chemotherapy was lacking. Survival data and the rate of patients entered onto clinical trials are acceptable; however, further improvements can be made by the institution of multidisciplinary clinics and the education of referring clinicians.

Fludarabine and mitoxantrone: effective and well-tolerated salvage therapy in relapsed indolent lymphoproliferative disorders.

BACKGROUND: Prior studies of the combination of fludarabine, mitoxantrone and dexamethasone have yielded high response rates but are associated with a significant risk of opportunistic infections, predominantly Pneumocystis Carinii pneumonia (PCP) requiring routine prophylaxis. PATIENTS AND METHODS: We evaluated the combination of fludarabine (25 mg/m2/day x 3) and mitoxantrone (10 mg/m2 x 1) without corticosteroids or PCP prophylaxis in 29 patients with relapsed or refractory indolent lymphoproliferative disorders; median age 56 years, 62% refractory to preceding chemotherapy. RESULTS: A median of four cycles was administered without cumulative myelosuppression. Neutropenia <0.5 x 10(9/)l was seen in 16% of cycles. Infections complicated 10.4% of cycles. with impaired performance status (> or = ECOG 2) and increased age ( > 56 years) significant risk factors (P < or = 0.01). No cases of PCP were encountered. The response rate was 90%, median remission duration 11.9 months and the median survival 57 months. Peripheral blood progenitor cell mobilization was attempted in 11 patients and yielded > or = 2 x 10(6) CD34+ cells/kg in only 5 cases (45%). CONCLUSIONS: High response rates can be attained with fludarabine and mitoxantrone in combination without corticosteroids, and routine PCP prophylaxis can safely be omitted. Peripheral blood progenitor collections are problematic in these heavily pretreated patients.

Enhancement of platelet recovery after myelosuppressive chemotherapy by recombinant human megakaryocyte growth and development factor in patients with advanced cancer.

PURPOSE: To explore the influence of dose and schedule on the ability of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) to abrogate thrombocytopenia after multiple cycles of chemotherapy and to mobilize peripheral-blood progenitor cells (PBPC). PATIENTS AND METHODS: In this open-label study, 68 patients with advanced cancer were randomized to receive PEG-rHuMGDF subcutaneously at different doses and durations before administration of carboplatin 600 mg/m(2), cyclophosphamide 1,200 mg/m(2), and filgrastim 5 microgram/kg/d. PEG-rHuMGDF was not given after the first cycle of chemotherapy but was given after the second and subsequent cycles. Chemotherapy was given every 28 days for up to six cycles. RESULTS: In patients who received the same dose of chemotherapy for at least two cycles, the platelet nadir was significantly higher (47.5 x 10(9)/L v 35.5 x 10(9)/L; P =.003) and duration of grade 3 or 4 thrombocytopenia significantly shorter (0 v 3 days; P =.004) when PEG-rHuMGDF was administered after chemotherapy. There was no evidence of an effect of PEG-rHuMGDF when it was given before chemotherapy. Platelet recovery after the first cycle of chemotherapy was no different for different PEG-rHuMGDF regimens, and there was no difference between patients treated with PEG-rHuMGDF and historical controls treated with identical chemotherapy. There was a modest dose-related increase in progenitor cell levels after administration of PEG-rHuMGDF alone. Peak levels of PBPC occurred later in cycle 2 than in cycle 1 but were not different in magnitude. CONCLUSION: PEG-rHuMGDF abrogated severe thrombocytopenia after dose-intensive chemotherapy. However, it had only a modest effect on progenitor cell levels and did not enhance progenitor cell mobilization after chemotherapy and filgrastim.

Human rotation-mediated fetal mixed brain cell aggregate culture: characterization and N-methyl-D-aspartate toxicity.

One difficulty in generating in vitro models of neuropathogenesis lies in maintaining stable proportions of primary neurons within a mixed brain cell population. Rotation-mediated fetal brain aggregate culture has been modified to permit growth of human primary fetal brain cells containing 50 to 60% neurons. After 12 weeks cholinesterase, neuron specific enolase and microtubule-associated protein-2 were demonstrable by biochemical assay and immunocytochemical labelling of cryostat sections of human fetal brain aggregates. Upon exposure to the glutamate agonist; N-methyl-D-aspartate for 7 days at 35 days in vitro neuron specific enolase and cholinesterase decreased to 60 to 70% of untreated levels. Glial fibrillary acidic protein did not change significantly but swollen astrocytes were seen in labelled sections of treated aggregates. This method is useful to study human neurotoxicity and degeneration in mixed glial culture without astrocyte overgrowth.

A phase I and pharmacokinetic study of subcutaneously-administered recombinant human interleukin-4 (rhuIL-4) in patients with advanced cancer.

PURPOSE: To investigate the pharmacokinetics and tolerability of recombinant human interleukin-4 (rhuIL-4), administered by daily subcutaneous injection, in patients with advanced cancer. PATIENTS AND METHODS: Fourteen patients with advanced cancer treated with rhuIL-4 at escalating dose levels of 0.25, 1.0 and 5.0 microg/kg/day, on days 1, 8-17, and 28-57. The primary endpoints of the study were toxicity of rhuIL-4 and the determination of the pharmacokinetics of rhuIL-4 when given by subcutaneous injection. Secondary endpoints included effects on blood counts, hematopoietic cell precursors, and various immunologic parameters. RESULTS: rhuIL-4 was well tolerated at all three dose levels. Detectable serum levels of IL-4 were found in patients at the 1.0 and 5.0 microg/kg/day dose levels. Peak serum IL-4 levels were achieved about 2 h after injection and IL-4 was still detectable 8 h after injection. No grade 4 toxicities were observed and grade 3 toxicities were confined to fever, headache and raised hepatic alkaline phosphatase. No consistent hematological or immunologic effects were observed. Although therapeutic efficacy was not an endpoint, one complete response (Hodgkin's disease) was observed. One patient with chronic lymphocytic leukemia progressed on therapy. CONCLUSION: rhuIL-4 up to 5.0 microg/kg/day is well tolerated when given by subcutaneous injection. Biologically relevant serum IL-4 levels can be achieved and sustained for at least 8 h after a single injection.

Randomized cross-over trial of progenitor-cell mobilization: high-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF.

PURPOSE: Patient response to hematopoietic progenitor-cell mobilizing regimens seems to vary considerably, making comparison between regimens difficult. To eliminate this inter-patient variability, we designed a cross-over trial and prospectively compared the number of progenitors mobilized into blood after granulocyte-macrophage colony-stimulating factor (GM-CSF) days 1 to 12 plus granulocyte colony-stimulating factor (G-CSF) days 7 to 12 (regimen G) with the number of progenitors after cyclophosphamide plus G-CSF days 3 to 14 (regimen C) in the same patient. PATIENTS AND METHODS: Twenty-nine patients were randomized to receive either regimen G or C first (G1 and C1, respectively) and underwent two leukaphereses. After a washout period, patients were then crossed over to the alternate regimen (C2 and G2, respectively) and underwent two additional leukaphereses. The hematopoietic progenitor-cell content of each collection was determined. In addition, toxicity and charges were tracked. RESULTS: Regimen C (n = 50) resulted in mobilization of more CD34(+) cells (2.7-fold/kg/apheresis), erythroid burst-forming units (1.8-fold/kg/apheresis), and colony-forming units-granulocyte-macrophage (2.2-fold/kg/apheresis) compared with regimen G given to the same patients (n = 46; paired t test, P<.01 for all comparisons). Compared with regimen G, regimen C resulted in better mobilization, whether it was given first (P =.025) or second (P =.02). The ability to achieve a target collection of > or =2x10(6) CD34(+) cells/kg using two leukaphereses was 50% after G1 and 90% after C1. Three of the seven patients in whom mobilization was poor after G1 had > or =2x10(6) CD34(+) cells/kg with two leukaphereses after C2. In contrast, when regimen G was given second (G2), seven out of 10 patients failed to achieve the target CD34(+) cell dose despite adequate collections after C1. Thirty percent of the patients (nine of 29) given regimen C were admitted to the hospital because of neutropenic fever for a median duration of 4 days (range, 2 to 10 days). The higher cost of regimen C was balanced by higher CD34(+) cell yield, resulting in equivalent charges based on cost per CD34(+) cell collected. CONCLUSION: We report the first clinical trial that used a cross-over design showing that high-dose cyclophosphamide plus G-CSF results in mobilization of more progenitors then GM-CSF plus G-CSF when tested in the same patient regardless of sequence of administration, although the regimen is associated with greater morbidity. Patients who fail to achieve adequate mobilization after regimen G can be treated with regimen C as an effective salvage regimen, whereas patients who fail regimen C are unlikely to benefit from subsequent treatment with regimen G. The cross-over design allowed detection of significant differences between regimens in a small cohort of patients and should be considered in design of future comparisons of mobilization regimens.

Multi-purpose silastic dual-lumen central venous catheters for both collection and transplantation of hematopoietic progenitor cells.

Autologous peripheral blood progenitor cell (PBPC) transplantation frequently requires sequential placement and use of two separate central venous catheters: (1) a short-term, large-bore, stiff device inserted for leukapheresis, and after removal of that device, (2) a long-term, multi-lumen, flexible, Silastic catheter for administration of high-dose chemotherapy, re-infusion of hematopoietic cells, and intensive supportive care. We reviewed our recent experience with two dual-lumen, large-bore, Silastic multi-purpose ('hybrid') catheters, each of which can be used as a single device for both leukapheresis and long-term supportive care throughout the transplant process. Quinton-Raaf PermCath and Bard-Hickman hemodialysis/apheresis dual-lumen catheters were used as the sole venous access device in 112 consecutive patients who underwent autologous PBPC collection and transplantation. The catheter exit site was monitored three times a week, and lumen patency was assessed using clinical and radiologic techniques. Catheters were removed prematurely for persistent thrombus, positive blood cultures despite appropriate antibiotics, or mechanical dysfunction. There were no intra-operative or immediate post-operative complications relating to insertion. Thirty-two patients experienced catheter occlusion necessitating urokinase instillation. Persistent occlusive problems were noted in 16 patients, and in 10 patients the catheter had to be removed. Two exit site infections and 17 bacteremias occurred. Catheters had to be removed for persistent infection in two subjects and for mechanical problems in five others. Cost analysis comparing the hybrid catheters alone vs conventional devices revealed a charge of $4230 in patients with hybrid catheters vs. $7530 in those requiring a temporary non-Silastic dialysis catheter in addition to a flexible, long-term Silastic catheter. Hybrid, Silastic, dual-lumen, large-bore central venous catheters are safe, cost-effective and convenient multi-purpose venous access devices that may be used in the setting of autologous PBPC collection and transplantation. The rate of thrombotic, infectious and mechanical complications appears comparable to other central venous access devices.

The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its metabolites on rat brain spheroids in culture.

Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity of methylenedioxy-methamphetamine (MDMA, Ecstasy) and two of its metabolites, dihydroxymethamphetamine (DHMA) and 6-hydroxy-MDMA (6-OH MDMA). Exposure of brain spheroids to MDMA or the metabolite 6-OH MDMA (up to 500 micromol/L) for 5 days in culture did not alter intracellular levels of glutathione (GSH), glial fibrillary acidic protein (GFAP) or serotonin (5-HT). In contrast, exposure to the metabolite DHMA, which can deplete intracellular thiols, significantly increased GSH levels (up to 170% of control) following exposure to 50 and 100 micromol/L DHMA. There was also a significant reduction in the levels of glial fibrillary acidic protein (GFAP) and GSH by DHMA at the highest concentration tested (500 micromol/L) but there was no effect on 5HT. This may constitute a sublethal neurotoxic compensatory response to DHMA in an attempt to replenish depleted intraneural GSH levels following metabolite exposure. Rat whole-brain spheroids may thus be a useful in vitro model to delineate mechanisms and effects of this class of neurotoxin.

KRN8602 (MX2-hydrochloride): an active new agent for the treatment of recurrent high-grade glioma.

PURPOSE: To assess the efficacy and toxicity of KRN8602 when administered as an intravenous bolus to patients with recurrent high-grade malignant glioma. PATIENTS AND METHODS: Patients with recurrent or persistent anaplastic astrocytoma or glioblastoma multiforme who had not received recent chemotherapy or radiotherapy and were of good performance status (Eastern Cooperative Oncology Group score < or = 2) were treated with an intravenous bolus of 40 mg/m(2) KRN8602 every 28 days. Tumor responses were assessed radiologically and clinically after every second cycle of therapy. Treatment was continued until documented progression or a total of six cycles. RESULTS: A median of three cycles (range, one to six cycles) of KRN8602 was administered to 55 patients, 49 of whom received at least two cycles and were, therefore, assessable for response. The overall response rate (disease stabilization or better) was 43% (95% confidence interval, 29% to 58%). There were three complete responses, one partial response, seven minor responses, and 10 patients with stable disease. The median time to progression was 2 months (range, 1.5 to 37 months) and overall survival was 11 months (range, 1.5 to 40 months). Neutropenia was the most common toxicity, although it was generally of brief duration, and there were only seven episodes of febrile neutropenia in 176 cycles delivered. Nonhematologic toxicity was mostly gastrointestinal (nausea and vomiting, diarrhea) and events were grade 2 or lower except for a single episode of grade 3 vomiting. CONCLUSION: KRN8602 is an active new agent with minimal toxicity in the treatment of relapsed or refractory high-grade glioma. Further studies with KRN8602 in combination with other cytotoxics and in adjuvant treatment of gliomas are warranted.

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors.

BACKGROUND: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages. RESULTS: The MTD in stage I was epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m2, cyclophosphamide 1500 mg/m2, vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir < 0.5 x 10(9)/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (< 25 x 10(9)/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity. CONCLUSION: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.

Multicycle high-dose chemotherapy and filgrastim-mobilized peripheral-blood progenitor cells in women with high-risk stage II or III breast cancer: five-year follow-up.

PURPOSE: To determine the safety and efficacy of multiple cycles of dose-intensive, nonablative chemotherapy in women with poor-prognosis breast cancer. PATIENTS AND METHODS: Women with stage II breast cancer and 10 or more involved nodes or four or more involved nodes and estrogen receptor-negative tumors and women with stage III disease received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2, with progenitor cell and filgrastim support every 28 days (n = 79) or 21 days (n = 20). Patients were reviewed at least twice yearly thereafter. Twenty-six patients had bone marrow and apheresis collections assessed for the presence of micrometastatic tumor cells. RESULTS: Ninety-nine women (median age, 43 years; range, 24 to 60 years) were treated. Ninety-two completed all three cycles of chemotherapy. The major toxicity was severe, reversible myelosuppression that was more prolonged with successive cycles, and this did not differ between patients given treatment every 28 days and those treated every 21 days. Febrile neutropenia occurred in 176 (61%) of 287 cycles. Severe mucositis (grade 3 or 4) occurred in 23% of cycles but tended to be short-lived and was reversible. The cardiac ejection fraction fell by a median of 4% during treatment, and three patients developed evidence of cardiac failure after chemotherapy. Two patients (2%) died of acute toxicity. Three of 26 patients had evidence of circulating micrometastatic tumor cells. The actuarial distant disease-free and overall survival rates at 60-month follow-up were 64% (95% confidence interval [CI], 53% to 75%) and 67% (95% CI, 56% to 78%), respectively. CONCLUSION: Multiple cycles of dose-intensive, nonablative chemotherapy is a feasible and safe approach. Disease control and survival are similar to those in other studies of myeloablative chemotherapy in poor-prognosis breast cancer. The regimen is being evaluated in a randomized trial of the International Breast Cancer Study Group.

Reconstruction of a neocondyle using transport distraction osteogenesis.

The process of slow bone expansion by distraction osteogenesis in conjunction with functional remodeling can also be used for the reconstruction of a neomandible and neocondyle. This is the technique of transport distraction osteogenesis. A transport disc is surgically created adjacent to the area of a discontinuity defect, and the transport disc is advanced by the process of distraction osteogenesis, using the Ilizarov principles. The mandible therefore acts as the bony template for reconstruction such that the neomandible created from the distraction process has the same size and shape as the native mandible covered by gingiva. This allows for enhanced prosthetic reconstruction. A reverse-L osteotomy of the ramus can also be performed to create a transport disc to reconstruct a neocondyle. Because the leading edge of the transport disc becomes enveloped by a fibrocartilagenous cap, the ramal transport disc can be moved superiorly to create a new articulation. Patients are encouraged to open and close their mouths during the distraction process, such that the transport disc remodels to form a neocondyle. This technique was successfully used to treat patients with degenerative joint disease, condylar resorption, and bony ankylosis.

Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer.

PURPOSE: To prospectively evaluate the long term cardiac effects of high-dose epirubicin and cyclophosphamide given to women with early stage, poor prognosis breast cancer. PATIENTS AND METHODS: Women with stage 2 breast cancer and 10+ nodes or 4+ nodes and estrogen receptor negative tumor, or stage 3 breast cancer received three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 gm/m2 with peripheral blood progenitor cell and filgrastim support. Treatment was given every 28 days (n = 79) or 21 days (n = 20). Fifty patients received radiotherapy to the chest wall or breast, 25 of to the left side. Patients were assessed clinically regularly during chemotherapy and at least three times yearly after completion of treatment. Cardiac left ventricular ejection fraction (LVEF) was assessed by radionuclide scan before therapy, after each cycle of chemotherapy, three months and six months after completion of chemotherapy, and yearly thereafter until relapse. RESULTS: Ninety-nine women were treated, and 92 completed all three cycles of chemotherapy. The median age was 43 years (range 24 to 60 years). All patients were included in this analysis. The median relapse-free survival was 39 months (11 to 68 months). There was a significant fall in LVEF during chemotherapy. In general, there was no further deterioration in cardiac function from the third month after cessation of treatment, however there was substantial variation between individuals. 35 patients had at least one LVEF measure less than normal (< 50%), but the LVEF returned to normal in 20 of these with further follow-up. Cardiac dysfunction was not increased in women who received radiotherapy and was not different between cohorts given chemotherapy every three or every four weeks. One patient died of acute myocardial necrosis following the third cycle of chemotherapy. Two patients developed clinical evidence of cardiac failure, and another had radiological signs but was asymptomatic. One woman died of progressive cardiac failure, one recovered clinically but also developed recurrent breast cancer, while the third recovered after commencement of medical therapy. CONCLUSIONS: During follow-up after high-dose epirubicin and cyclophosphamide as delivered in this study, the LVEF fell to below normal in approximately one third of patients. However, in over half of these patients the LVEF subsequently recovered to the normal range, and the incidence of clinically evident chronic cardiac failure was low. Further follow-up is required to assess the long-term safety. A randomized comparison with standard-dose anthracycline-based chemotherapy is needed to determine whether this regimen is associated with an increased risk of clinical cardiac toxicity.