The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up.

BACKGROUND: The role of adjuvant dose-intensive chemotherapy and its efficacy according to baseline features has not yet been established. PATIENTS AND METHODS: Three hundred and forty-four patients were randomized to receive seven courses of standard-dose chemotherapy (SD-CT) or three cycles of dose-intensive epirubicin and cyclophosphamide (epirubicin 200 mg/m(2) plus cyclophosphamide 4 mg/m(2) with filgrastim and progenitor cell support). All patients were assigned tamoxifen at the completion of chemotherapy. The primary end point was disease-free survival (DFS). This paper updates the results and explores patterns of recurrence according to predicting baseline features. RESULTS: At 8.3-years median follow-up, patients assigned DI-EC had a significantly better DFS compared with those assigned SD-CT [8-year DFS percent 47% and 37%, respectively, hazard ratio (HR) 0.76; 95% confidence interval 0.58-1.00; P = 0.05]. Only patients with estrogen receptor (ER)-positive disease benefited from the DI-EC (HR 0.61; 95% confidence interval 0.39, 0.95; P = 0.03). CONCLUSIONS: After prolonged follow-up, DI-EC significantly improved DFS, but the effect was observed only in patients with ER-positive disease, leading to the hypothesis that efficacy of DI-EC may relate to its endocrine effects. Further studies designed to confirm the importance of endocrine responsiveness in patients treated with dose-intensive chemotherapy are encouraged.

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.

Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy.

PURPOSE: We evaluated the toxicity and pharmacokinetics of the combination of dexrazoxane with epirubicin at dexrazoxane/epirubicin dose ratios of 5 to 9:1 in a controlled, crossover phase I study in patients with advanced malignancy. PATIENTS AND METHODS: Thirty-eight patients with a variety of malignancies were enrolled. Assessable patients received two cycles of chemotherapy consisting of epirubicin alone and in combination with dexrazoxane. Comparisons were made between the toxicity and pharmacokinetics of epirubicin in the two treatment arms, using each patient as his or her own control. Dexrazoxane and epirubicin were delivered at dose levels of 600/120 mg/m2, 900/120 mg/m2, 900/135 mg/m2, 900/150 mg/m2, and 1,200/135 mg/m2, respectively. Twenty-six patients completed two cycles of chemotherapy and were therefore assessable. RESULTS: The maximum-tolerated doses (MTDs) of dexrazoxane/epirubicin were 1,200/135 mg/m2, with the dose-limiting toxicities being neutropenia, infection, and stomatitis. There was no difference in the nadir neutrophil or platelet counts between single-agent and combination treatment at any of the dose levels. Severe vomiting and stomatitis occurred less frequently following administration of epirubicin and dexrazoxane when compared with epirubicin alone (P = .01 and .02, respectively). Prior administration of higher doses (900 mg/m2 and 1,200 mg/m2) of dexrazoxane increased the systemic clearance of epirubicin, resulting in a decrease in the area under the curve (AUC). Elimination half-life, maximum plasma concentration (Cmax), and apparent volume of distribution of epirubicin were not significantly affected by dexrazoxane. Left ventricular ejection fraction (LVEF) decreased by greater than 10% in two patients, but neither developed clinical or radiologic evidence of cardiac failure. CONCLUSION: This study demonstrates that dexrazoxane can be safely combined with escalating doses of epirubicin at dose ratios of 5 to 9:1 without having an adverse impact on toxicity. Studies are need to determine the optimal dose ratio for cardioprotection and to explore further the pharmacokinetic interactions of the two drugs at increasing doses of epirubicin supported by hematopoietic growth factors.

Phase I and pharmacokinetic study of KRN8602 alone and with filgrastim in patients with advanced cancer.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of KRN8602 (MX2-hydrochloride), a novel morpholino anthracycline with potent cytotoxicity against anthracycline-sensitive and resistant experimental tumors in vitro and in vivo. PATIENTS AND METHODS: KRN8602 was administered alone in increasing doses to patients with advanced cancer or high-grade gliomas until dose-limiting toxicity (DLT) was observed in three or more of five patients treated in a dose level. Because neutropenia was dose limiting, further escalation was investigated with filgrastim support. RESULTS: Fifty-six assessable patients completed at least one cycle of chemotherapy. The recommended dose of KRN8602 alone was 40 mg/m2. Dose escalation was limited by neutropenia. The recommended dose of KRN8602 with filgrastim was 70 mg/m2, and limiting toxicities were neutropenia, diarrhea, and vomiting. The most commonly experienced nonhematologic toxicity was nausea and vomiting. Alopecia and mucositis were infrequent and mild. Pharmacokinetic parameters showed substantial variation, although the area under the plasma concentration-time curve (AUC) and maximum concentration both increased with dose. There was no relationship between pharmacokinetic parameters and toxicity. CONCLUSION: KRN8602 at doses of 40 mg/m2 when administered alone and 70 mg/m2 when administered with filgrastim appeared to be manageable. The major DLTs were neutropenia and, at higher doses, diarrhea and vomiting. The efficacy of this drug is currently being tested in phase II studies.

Phase I and pharmacokinetic study of photodynamic therapy for high-grade gliomas using a novel boronated porphyrin.

PURPOSE: To determine the recommended dose, toxicity profile, and pharmacokinetics of a novel boronated porphyrin (BOPP) for photodynamic therapy (PDT) of intracranial tumors. PATIENTS AND METHODS: BOPP was administered alone in increasing doses (0.25, 0.5, 1.0, 2.0, 4.0, or 8.0 mg/kg) preoperatively in patients with intracranial tumors undergoing postresection PDT until dose-limiting toxicity (DLT) was observed. RESULTS: Twenty-nine assessable patients with intracranial tumors received BOPP intravenously 24 hours before surgery. The recommended dose was 4 mg/kg. Dose escalation was limited by thrombocytopenia. The most common nonhematologic toxicity was skin photosensitivity. Pharmacokinetic parameters showed increased area under the plasma concentration-time curve and maximum concentration with increased dose. Tumor BOPP concentrations also increased with increased dose. CONCLUSION: BOPP at a dose of 4 mg/kg was well tolerated. DLT was thrombocytopenia, and photosensitivity was the only other toxicity of note. The efficacy of PDT using BOPP requires further exploration.

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.

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.

Rapid hematopoietic recovery after multicycle high-dose chemotherapy: enhancement of filgrastim-induced progenitor-cell mobilization by recombinant human stem-cell factor.

PURPOSE: To assess the mobilization potential and safety of recombinant human stem-cell factor (SCF) when coadministered with filgrastim to untreated women with poor-prognosis breast cancer. PATIENTS AND METHODS: Eligible women had breast cancer with 10 or more positive axillary nodes, or estrogen receptor-negative tumor with 4 positive nodes, or stage III disease. Patients were randomized to receive SCF plus filgrastim or filgrastim alone. Filgrastim 12 microg/kg daily was administered for 6 days by continuous subcutaneous infusion. SCF was administered by daily subcutaneous injection at 5, 10, or 15 microg/kg concurrent with filgrastim for 7 days, or 10 microg/kg daily starting 3 days before filgrastim for a total of 10 days (SCF pretreatment). Apheresis was performed on days 5, 6, and 7 of filgrastim administration. Patients then had three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2 every 28 days, each supported by one third of the apheresis product. RESULTS: Sixty-two women were treated. Greater yields occurred in patients who received SCF 10 microg/kg daily plus filgastim than those who received filgrastim alone (P=.013 for CD34+ cells; P=.07 for granulocyte-macrophage colony-forming cells [GM-CFCs]). The difference was more marked with SCF-pretreatment than concurrent SCF. Fewer aphereses were required to reach the predetermined target of peripheral-blood progenitor/stem cells (PBPCs) in women who received SCF. SCF was generally well tolerated. Hematologic recovery was rapid after each of the three cycles of chemotherapy. There was no difference in recovery between the different treatment groups. CONCLUSION: Mobilization of PBPCs by filgrastim is significantly enhanced by coadministration of SCF, and commencing SCF before filgrastim can optimize this effect. SCF has the potential to reduce the number of aphereses required to collect a target number of PBPCs.

Adjuvant treatment of high-risk breast cancer using multicycle high-dose chemotherapy and filgrastim-mobilized peripheral blood progenitor cells.

Women with primary breast cancer associated with extensive axillary node involvement or large primary tumors have a very poor prognosis despite treatment with standard-dose adjuvant chemotherapy. In an attempt to improve the outlook of these patients, we investigated the safety and feasibility of delivering three cycles of high-dose epirubicin and cyclophosphamide supported with filgrastim-mobilized peripheral blood progenitor cells (PBPC). Fifteen previously untreated women, median age 50 (range, 30-58) years, with poor prognosis early stage breast cancer received filgrastim (12 microgram/kg daily for 6 days) prior to chemotherapy to mobilize progenitor cells. Patients were then given three cycles of epirubicin (200 mg/m2) and cyclophosphamide (4 g/m2) at planned 28-day intervals, each followed by infusion of one third of the PBPC collected and daily administration of filgrastim (5 microgram/kg s.c.). Three leukaphereses collected a median of 114.9 (range, 22.7-273.5) x 10(4) granulocyte-macrophage-colony-forming cells/kg body weight. Hemopoietic recovery was rapid after each cycle, and there was no correlation between the rate of recovery and the number of granulocyte-macrophage-colony-forming cells infused. There was a small but significant progressive delay in recovery from hematological and nonhematological toxicities across the three cycles. Left ventricular ejection fraction fell to below 50% in eight (53%) patients, but none developed congestive cardiac failure. Two patients did not complete three cycles because of insufficient PBPC for a third cycle (n = 1) and 2-mercaptoethane sodium sulfonate- related drug reaction during the second cycle (n = 1). There were no deaths during the study or during the follow-up period (median, 70 weeks; range, 50-85 weeks), and no late toxicities occurred. Therefore, we concluded that the delivery of multiple cycles of nonmyeloablative, dose-intensive chemotherapy supported by PBPC and filgrastim is safe, and may be widely applicable to a variety of common chemosensitive cancers with a poor prognosis. The efficacy of three cycles of high-dose epirubicin and cyclophosphamide is to be compared with standard-dose chemotherapy in a randomized trial in patients with high-risk, operable stage II and III breast cancer.

Biologic and structural differences of thrombopoietic growth factors.

The search for a thrombopoietic agent has resulted in the identification of numerous cytokines and growth factors with thrombopoietic activity. However, with the exception of interleukin (IL)-11 and thrombopoietin (TPO), the megakaryopoietic activity of most of these molecules has not produced clearly identifiable clinical benefits. Despite the relatively modest effect of IL-11 on megakaryocyte and platelet production in vitro and in vivo, it does reduce the need for platelet transfusions in specialized clinical settings. In contrast, the c-Mpl ligand TPO has been shown to be a potent stimulator of megakaryocyte and platelet production both in vitro and in vivo. Clinical studies are being conducted with two different preparations of the c-Mpl ligand: recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). A recombinant form of the complete human molecule, rhTPO is glycosylated and produced in mammalian cells. PEG-rHuMGDF consists of only the receptor-binding domain linked to a polyethylene glycol (PEG) moiety and is generated in Escherichia coil. Although c-Mpl ligands are still being evaluated, preliminary evidence indicates that these molecules can elevate platelet counts and may be useful in a range of clinical contexts. This report discusses aspects of the biology behind the clinical actions of IL-11 and the c-Mpl ligands.

A risk-benefit assessment of anthracycline antibiotics in antineoplastic therapy.

The anthracycline antibiotics comprise a group of cytotoxic compounds with wide-ranging activity against human malignancies. They are used extensively for curative, adjuvant and palliative therapy, both as single agents and in combination regimens. They produce a number of adverse effects, some of which are shared by other cytotoxic drugs. The most important adverse effect is cardiotoxicity, which is unique to this class of compounds. Strategies have been devised to circumvent these adverse effects, including the development of less toxic analogues, alterations in scheduling, the addition of cardioprotectant agents and methods of monitoring for cardiac abnormalities.

Failing to live up to the fanfare? A personal perspective on obstacles to the clinical development of thrombopoietic agents.

A number of hematopoietic growth factors have been identified that are active on megakaryocytes and platelets, but only 2, interleukin-11 (IL-11) and thrombopoietin, are being actively pursued clinically, with IL-11 approved for treatment of thrombocytopenia. The development of these agents in general has been disappointing, and in part this reflects the inherent biology of these factors with a failure to match clinical need with physiological function. The delayed action of these factors is also a consequence of the intrinsic biology of megakaryocytes and platelets, and thus is likely to be limiting regardless of which factor is employed. In addition, the development of these agents has occurred at a time when there is something of a decreasing demand for platelets, at least in the context of chemotherapy-induced thrombocytopenia. This decrease is the result of increased use of blood stem cells to support intensive chemotherapy procedures, reduced thresholds for platelet transfusion, and a decreasing role for intensive chemotherapy. These issues are discussed.

Thrombopoietin: an update on therapeutic potential.

Thrombopoietin (TPO), the central regulator of megakaryocytopoiesis, was first identified in 1994 and since then much has been learnt about megakaryocyte and platelet physiology. Two forms of TPO have entered clinical trials, the full length recombinant version (rhTPO) and a truncated form (megakaryocyte growth and development factor, MGDF). Both have equivalent biological activity in preclinical studies and both have been demonstrated to have potent biological activity in humans. TPO and MGDF administration cause a dose-dependent increase in platelet count with no effect on white cell count or haematocrit. These platelets are morphologically and functionally normal. When administered following myelosuppressive chemotherapy, MGDF and TPO significantly enhance platelet recovery, although scheduling in relation to chemotherapy may be important in optimising the full effects. TPO and MGDF mobilise progenitor cells of multiple haematopoietic lineages and may enhance the effects of filgrastim on peripheral blood progenitor cell levels after chemotherapy. Both forms of TPO are well tolerated and cause few acute toxicities. Numerous studies are underway to help determine the precise role of TPO in clinical practice.

Pilot study of escalating doses of carboplatin and cyclophosphamide in patients with advanced cancer.

In all, 18 patients with histologically proven advanced cancer received 400 mg/m2 carboplatin (CBDCA) plus 800 mg/m2 cyclophosphamide (level 1), and 14 others received 550 mg/m2 CBDCA plus 1100 mg/m2 cyclophosphamide (level 2). A maximum of six cycles was given if a response occurred. The dose-limiting toxicity was myelosuppression, with neutropenia being more marked than thrombocytopenia. At level 2, patients experiencing a febrile-neutropenic event showed a mean 24-h urinary creatinine clearance value of 1.1 ml/s (95% confidence limits 0.8-1.4 ml/s), whereas in those who remained afebrile it was 1.7 ml/s (95% confidence limits, 1.3-2.0 ml/s). This difference was significant (P less than 0.01). Other toxicities were only mild. Creatinine clearance is a predictor of febrile episodes after treatment with high doses of CBDCA and cyclophosphamide. We are now conducting a study using human granulocyte colony-stimulating factor to reduce the incidence of neutropenia with escalating doses of these drugs in an attempt to prevent febrile events.

Pharmacokinetics and pharmacodynamics of MX2 hydrochloride in patients with advanced malignant disease.

The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10-50 mg/m2 (total dose 16.8-107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 +/- 1.68 l/min, the mean volume of distribution at steady state was 1460 +/- 749 l and mean elimination half-life was 10.8 +/- 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r2 = 0.43, P < 0.01 and r2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 +/- 5.0, 21.9 +/- 11.8, 19.0 +/- 11.3 and 12.3 +/- 6.3 h, respectively. The fractional Emax model produced a much better fit to the relative nadir neutrophil count versus dose data (r2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (Cmax) data (r2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 x 10(9)/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and Cmax than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or Cmax.

Effect of filgrastim on the pharmacokinetics of MX2 hydrochloride in patients with advanced malignant disease.

PURPOSE: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. METHODS: A total of 25 patients with advanced malignant disease participated in a dose-escalation study in the first cycle of treatment given i.v. at doses of 50-80 mg/m2 (74-152 mg) with concomitant filgrastim (G-CSF, 5 microg/kg) given daily beginning at 24 h after the dose of MX2. RESULTS: The mean fast distribution half-life (1.5 +/- 1.0 min) and the mean plasma clearance (2.18 +/- 0.95 l/min) were significantly lower than the respective mean values found in a previous study in which 27 patients had received MX2 (16.8-107.5 mg) alone (3.3 +/- 2.2 min and 2.98 +/- 1.68 l/min, respectively; P < 0.05). There was no correlation between plasma clearance and the delivered dose for the combined MX2-alone and MX2-filgrastim groups, indicating that the lower clearance observed in the G-CSF group was probably not due to the higher dose. Elimination half-lives of the metabolites M1 and M4 were significantly greater in the filgrastim group (19.8 +/- 14.7 and 11.8 +/- 5.0 h for M1 and 14.8 +/- 4.1 and 12.3 +/- 6.3 h for M2, respectively). Unlike the MX2-alone group, there was no relationship in the MX2-filgrastim group between the relative nadir neutrophil count and the dose or between the duration of grade IV neutropenia and the dose of MX2. CONCLUSIONS: This study shows that filgrastim decreased the plasma clearance of MX2 by approximately 25%, possibly by inhibition of metabolism.

New developments in high-dose chemotherapy for breast cancer.

High-dose chemotherapy with autologous stem cell support as applied to the treatment of breast cancer has shown promise for over 15 years. Three main approaches have been used: (1) standard-dose induction chemotherapy followed by one or two cycles of myeloablative therapy, (2) multicycle nonablative combination chemotherapy, and (3) high-dose sequential chemotherapy using single agents at the maximum tolerated doses in rapid sequence. Each of these approaches has a strong biological rationale and is being pursued in randomized trials. Unfortunately, comparative data are limited and there is only one fully published randomized trial of the use of high-dose chemotherapy in metastatic breast cancer. This small study from South Africa showed a significant improvement in response rate and survival for women receiving high-dose chemotherapy compared to those given standard dose treatment. It is anticipated that results from larger studies in the USA and Europe evaluating the use of high-dose chemotherapy in metastatic breast cancer and in adjuvant treatment of poor-prognosis early-stage disease will be available within the next 2-3 years. A potentially important and related issue is that of tumor contamination of bone marrow and apheresis collections. Current data suggest that finding epithelial tumor cells with sensitive techniques (such as immunohistochemistry or polymerase chain reaction) gives prognostic information. However, it is not clear whether reinfusion of these cells after high-dose chemotherapy contributes to relapse of breast cancer. Unfortunately, understanding of the data is marred by a lack of standardization of assay methodology. Further work is needed to develop a widely accepted method for the detection of circulating tumor cells before the clinical relevance of such a finding can be meaningfully interpreted.

Isolated pleural effusion with hematopoietic cells of mixed lineage in a patient receiving granulocyte-colony-stimulating factor after high-dose chemotherapy.

A 43-yr-old woman with recently diagnosed breast carcinoma presented with a right pleural effusion after a cycle of adjuvant, high-dose chemotherapy supported by peripheral blood progenitor cells (PBPC) and granulocyte-colony-stimulating factor (G-CSF, Filgrastim). Cytologic examination of the pleural aspirate yielded highly cellular material composed predominantly of cells of myeloid and macrophage/monocytic lineages. Despite clinical concern of a malignant effusion, the combination of cytologic and immunophenotypic examination yielded the correct diagnosis of a nonneoplastic effusion related to underlying pleural inflammation and possibly the administration of G-CSF.

ApoAI-phosphatidylcholine infusion neutralizes the atherothrombotic effects of C-reactive protein in humans.

BACKGROUND: High-density lipoprotein (HDL) exerts a variety of anti-atherothrombotic functions, including a potent anti-inflammatory impact. In line, the direct pro-inflammatory effects of C-reactive protein (CRP) can be attenuated by HDL in vitro. OBJECTIVE: To evaluate whether this also holds true in humans, we assessed the ability of reconstituted HDL to neutralize CRP-mediated activation of coagulation and inflammation. METHODS: Fifteen healthy male volunteers received an infusion of recombinant human (rh)CRP (1.25 mg kg(-1) body weight). In eight of these volunteers, an infusion of human apoAI reconstituted with phosphatidylcholine (apoAI-PC; 80 mg kg(-1) body weight) preceded rhCRP infusion. RESULTS: Infusion of rhCRP alone elicited an inflammatory response and thrombin generation. In individuals who received apoAI-PC prior to rhCRP, these effects were abolished. Parallel tests in primary human endothelial cells showed that apoAI-PC preincubation with rhCRP abolished the CRP-mediated activation of inflammation as assessed by IL-6 release. Although we were able to show that rhCRP co-eluted with HDL after size-exclusion chromatography, plasmon surface resonance indicated the absence of a direct interaction between HDL and CRP. CONCLUSION: Infusion of apoAI-PC prior to rhCRP in humans completely prevents the direct atherothrombotic effects of rhCRP. These findings imply that administration of apoAI-PC may offer benefit in patients with increased CRP.