Consensus statement for cancer patients requiring intensive care support.

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients.

[Tumor-induced hypercalcemia]. / Tumorinduzierte Hyperkalzämie.

Hypercalcemia is in many cases a symptom of advanced stage malignant diseases due to increased resorption and reduced secretion. A slightly increased hypercalcemia is mostly asymptomatic but high calcium levels are associated with neurological, gastrointestinal, cardiac and renal symptoms. Important diagnostic tools are the determination of serum albumin and ionized calcium levels. Therapeutic intervention depends on the clinical symptoms as well as calcium levels. Furthermore, increase over time and duration of hypercalcemia has to be taken into account. The principles of treatment are sufficient fluid replacement and maintaining adequate diuresis. In addition, calcitonin, bisphosphonates and steroids are effective and widely used to decrease plasma calcium levels.

Diagnosis of invasive fungal infections in haematological patients by combined use of galactomannan, 1,3-ß-D-glucan, Aspergillus PCR, multifungal DNA-microarray, and Aspergillus azole resistance PCRs in blood and bronchoalveolar lavage samples: results of a prospective multicentre study.

High mortality rates of invasive fungal disease (IFD), especially invasive aspergillosis (IA), in immunocompromised haematological patients and current diagnostic limitations require improvement of detection of fungal pathogens by defining the optimal use of biomarkers and clinical samples. Concurrent bronchoalveolar lavage (BAL) and peripheral blood samples of 99 haematological patients with suspected IFD were investigated within a multicentre prospective study. Diagnostic performance of a galactomannan (GM) enzyme immune assay (EIA), a 1,3-ß-D-glucan assay (BDG), an Aspergillus PCR, and a multifungal DNA-microarray (Chip) alone or in combination were calculated. IFD were classified as proven (n=3), probable (n=34), possible (n=33), and no IFD (n=29) according to EORTC/MSG criteria. GM, PCR, and Chip showed superior diagnostic performance in BAL than in blood, whereas specificity of BDG in BAL was poor (48% (14/29)). The combination of GM (BAL) with BDG (blood) showed sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and DOR (diagnostic odds ratio) of 92% (34/37), 93% (27/29), 94%, 90%, and 153.0, respectively. Combining GM (BAL) with PCR (BAL) showed convincing diagnostic potential for diagnosing IA with sensitivity, specificity, PPV, NPV, and DOR of 85% (17/20), 97% (28/29), 94%, 90%, and 158.7. Addition of the DNA-microarray resulted in further detection of two mucormycetes infections. In 1 out of 15 Aspergillus DNA-positive samples a triazole resistance-mediating Cyp51A mutation was found. Combination of biomarkers is superior to their sole use in diagnosing IFD, particularly IA. Integrating blood and BAL samples into a diagnostic algorithm is an advantageous approach.

A controlled trial of intravenous immune globulin for the prevention of serious infections in adults with advanced human immunodeficiency virus infection.

BACKGROUND: Studies on human immunodeficiency virus-infected children suggest that high-dose immune globulin therapy might be beneficial in reducing the episodes of recurrent infections. In adults, comparable studies are not available. OBJECTIVE: To determine the efficacy of intravenous (IV) immune globulin therapy in preventing infections and reducing days with fever, as well as the duration and frequency of hospitalization for human immunodeficiency virus-infected adults, in a prospective, randomized outpatient clinical trial. METHODS: Adult patients who met Centers for Disease Control and Prevention criteria B and C were randomized to be treated with (n = 70) or without (n = 57) IV immune globulin. Patients who were assigned to treatment with IV immune globulin received 400 and 200 mg/kg of this drug initially and every 21 days thereafter, respectively. Primary end points were the occurrence of laboratory-proved or clinically diagnosed infections and death caused by infection. RESULTS: In comparison with patients in the control group, IV immune globulin treatment significantly increased the time for which the patients who met Centers for Disease Control and Prevention criteria B and C were free from serious infection (P < .001). Twelve (17%) of the patients who received IV immune globulin had infection-related deaths compared with 20 (35%) of the control patients; however, this was not statistically significant (P = .06). Furthermore, immune globulin treatment was associated with an overall reduction in the number and duration of hospitalizations for short-term care (P = .002), days with fever (P < .001), and frequency of diarrhea (P < .001). Because of these results, the study was stopped by the local ethical board. CONCLUSION: Prophylactic IV immune globulin treatment in human immunodeficiency virus-infected adults decreases the frequency of serious infections and is associated with a reduction of hospitalization for short-term care.

New therapeutic modalities in the treatment of graft-versus-host disease.

Acute and chronic GvHD are still a major concern in allogeneic hematopoietic stem cell transplantation, still contributing substantially to morbidity and mortality in this therapeutic procedure. Over the past decade, many advances have been made with regard to the prevention and treatment of GvHD using various drugs such as cyclosporine A, FK506, mycophenolate mofetil and/or monoclonal IL-2 receptor antagonists. Despite these measurements with regard to the prevention of acute GvHD, it is very difficult to treat these clinical conditions successfully. However, if patients do not experience any GvHD often the desired effect of graft versus leukemia (GvL) remains absent increasing the probability of a relapse, in particular, in patients transplanted, which are considered at higher risk for relapse. At the present time, new strategies in the prevention of acute GvHD are in progress in particular the use of genetic manipulated donor T cells expressing suicide genes. Further clinical and laboratory studies are required in order to improve the prevention and, in particular, the therapy of established GvHD.

Factor XIII replacement in stem cell transplant (SCT) recipients with severe graft-versus-host disease of the bowel: report of an initial experience.

BACKGROUND: Severe acute graft-versus-host disease (aGVHD) of the gut is a serious and frequent posttransplantation event associated with a high mortality rate. We report on our experience with factor XIII replacement in patients with severe aGVHD of the bowel after allogeneic hematopoietic stem cell transplantation. METHODS: Twenty-seven patients after allogeneic stem cell transplantation and severe aGVHD of the gut were enrolled. All patients suffered from bloody diarrhea that required packed red blood cell infusions. All patients received high-dose immunosuppression in combination with coagulation factor XIII (5,000 units initially, followed by 20 IU/kg body weight three times a day) for up to 3 weeks. RESULTS: After 8 days of factor XIII replacement and unchanged high-dose immunosuppression, we observed a significant reduction in the red blood cell requirement of 21 patients. CONCLUSION: We conclude that factor XIII replacement might be a useful supplementation in the treatment of aGVHD of the bowel.

Inflammatory mediators in BAL fluid as markers of evolving pneumonia in leukocytopenic patients.

STUDY OBJECTIVES: Pneumonia during chemotherapy-induced leukocytopenia is a major cause of overall treatment failure in patients with hematologic malignancies. To improve outcome in these high-risk patients, early diagnosis of pulmonary infiltrates and institution of adequate antimicrobial treatment are mandatory. To identify patients with evolving pneumonia, we have prospectively studied the prognostic value of cytokine and complement measurements in early BAL samples from febrile leukocytopenic patients. DESIGN: Prospective, comparative study. SETTING: Hematology/oncology section of a university hospital. PATIENTS: Twenty-one patients with leukocytopenia (WBC count < 1.000/microL) following cytoreductive chemotherapy for malignant disorders. INTERVENTION: Early BAL sampling primarily for microbiologic diagnostic purposes. MEASUREMENTS AND RESULTS: Proinflammatory cytokines and activated complement components were measured in the BAL aspirates and the results were related to the prevalence or subsequent evolution of overt pneumonia. Of the 21 patients studied, 10 patients presented with overt pneumonia at BAL sampling (group A), 5 patients developed objective signs of pneumonia 3 to 5 days after BAL (group B), and 6 patients remained free of pneumonia during follow-up (group C). In comparison with group C, patients in groups A and B both had distinctly elevated bronchoalveolar levels of tumor necrosis factor-alpha, interleukin-6, granulocyte colony-stimulating factor, C3a, and C5a. CONCLUSIONS: Cytokine and complement determinations in early BAL samples may aid in the identification of febrile leukocytopenic patients with evolving pneumonia 3 to 5 days prior to the manifestation of diagnostic clinical and radiographic signs.

A comparative study of peripheral blood stem cell vs bone marrow transplantation from unrelated donors (MUD): a single center study.

Peripheral blood stem cell transplants (PBSCT) from unrelated donors (n = 37) were compared with bone marrow transplants (BM, bone marrow group, n = 37) in a matched pair analysis. Ten patients (2, class 1) in the alloPBSCT group and seven patients (2, class 1) in the BM group had one HLA locus mismatch donor, respectively. The following factors were matched: HLA-compatibility, diagnosis, disease stage, age and gender. The median age in the PBSC group was 37 years (19-56, excluding one 6-year-old child) and in the BM group 37 years (18-53). The BM group consisted of 12 females and 25 males, 17 females and 20 males were in the PBSC group. Twelve patients in the BM and 11 patients in the PBSC group were diagnosed with AMI,; 7/7, ALL; 15/15, CML; 2/3, MDS; 1/1, NHL. Thirty-four (14/20) of the 74 patients (45%) were considered as high risk patients. The conditioning regimen was BU/CY for standard risk patients with myeloid diseases (31 patients) and TBI/CY for ALL and NHL patients (36 patients); six patients received intensified conditioning with VP16 (2 patients), thiotepa (2 patients) or melphalan (1 patient). The GVHD prophylaxis regimen was used according to the Seattle protocol. DFS was 51% (19 patients) with a median of 352 days and 59% (21 patients) with a median of 760 days, in PBSC and BM transplants, respectively. The median time to leukocyte engraftment in PBSC patients was 14 days (range 6-26 days) and in the BM group 19 days (range 9-29 days; P < 0.02). The time of platelet engraftment did not differ significantly between the groups. The incidence of grade II-IV acute GVHD was 40% (four patients died, 13%) in the PBSC group and 20)% (three patients died, 8%) in the BM group, respectively (P < 0.05, log-rank). No signs of aGVHD were found in 19% of the patients in the PBSC and 27% in the BM group. Our results indicate that allogeneic PBSCT does lead to a significantly faster leukocyte engraftment. The significant increase with regard to the incidence and shorter time of onset of severe aGVHD in PBSC patients, compared to marrow transplant patients, need to be confirmed in a randomised trial.

Successful treatment of thrombocytopenia and hemolytic anemia with IvIG in a patient with lupus-like syndrome after mismatched related PBSCT.

Hematopoietic stem cell transplantation (HSCT) is a treatment option for autoimmune diseases but can also cause clinical features similar to those of autoimmune diseases. In some of these cases the autoimmune-like condition is associated with autoimmune cytopenia, a complication that can be unresponsive to established treatment strategies and which may be fatal. The majority of cases reported on immune hemolytic anemia have been of alloimmune origin due to ABO red blood cell antigen incompatibilities between donor and recipient. We now report a patient with a lupus-like syndrome, presenting with severe thrombocytopenia and hemolytic anemia 9 months after HLA-mismatch, ABO compatible-related PBSCT who experienced no response to high-dose steroids, but who had a sustained response to repeated IvIG therapy.

Reduced intensity preparative regimens for allogeneic hematopoietic stem cell transplantation: a single center experience.

According to recent reports, fast engraftment with minimal transplant-related toxicity and mortality (TRT, TRM) can be achieved by using reduced-intensity preparative regimens in allogeneic hematopoietic stem cell transplantation (HSCT). We report our experience with related (39%) and unrelated (61%) HSCT in 44 high risk patients (AML, ALL, CML, CLL) receiving either busulfan/fludarabine or busulfane/fludarabine/ATG or TBI/fludarabine as reduced-intensity preparative regimens. Organ toxicity was minimal with mild mucositis and no major bleeding. Acute GVHD was recorded in 64% of the patients. Twenty-three patients achieved complete remission after transplantation, and complete chimerism was obtained in all patients with stable engraftment (35 patients). Twenty-nine patients died: 15 due to relapse/progression, 14 due to TRM. Survival with median follow-up of 18.5 months was significantly better in patients with matched related transplants compared to patients with other transplants. However, there was no difference between related and unrelated transplants with regard to engraftment, TRM and GVHD. In conclusion, our results in high-risk patients transplanted in CR or with smoldering leukemia from a related donor are encouraging, although a longer follow-up and a larger group of patients is needed in order to evaluate the role of different reduced-intensity preparative regimens in unrelated and related HSCT.

New strategies in the treatment of graft-versus-host disease.

GVHD continues to be a major complication after allogeneic hematopoietic stem cell transplantation even when the recipient is given immunosuppression for the prophylaxis of this severe disease. There have been many advances in the prevention and treatment of GVHD, using compounds such as cyclosporine, FK506, mycophenolate mofetil or monoclonal IL-2 receptor antagonist. New strategies seem to include sequential therapy involving the blocking of both endogenous cytokines and alloreactive donor cells. However, further clinical and laboratory studies are needed in order to improve the therapy of established GVHD.

New strategies in GVHD prophylaxis.

Despite immunosuppressive therapy using cyclosporine (CsA) and prednisolone and methotrexate (MTX), the incidence for aGVHD grade II to IV after transplantation from HLA matched unrelated donors (MUD) is 78%, the incidence for grade III and IV 36%. Since GVHD contributes to morbidity and mortality after MUD-BMT, a more effective prophylactic regimen is needed in order to prevent these transplant-associated complications. Recently, we described that mycophenolate mofetil (MMF, CellCept), an immunosuppressive agent successfully used for the prevention of acute rejection in renal allograft recipients, can safely and effectively be used for the treatment of aGVHD in hematopoietic stem cell transplantation. Information on the i.v. formulation of mycophenolic acid (MPA) is not yet available. Here we report on the i.v. formulation of MMF in hematopoietic stem cell recipients. MMF is effective in the prophylaxis of acute GVHD after stem cell transplantation; the optimal dosage needs further investigation. At the present time the relevance of measurement of plasma MPA concentrations on MMF dosage is not yet understood and further evaluation is required.

Feasibility and safety of peripheral blood stem cell transplantation from unrelated donors: results of a single-center study.

We compared the outcomes in patients receiving unrelated peripheral blood stem cell transplants (PBSCT) with those receiving bone marrow transplants (BMT) in a matched pair analysis. Seventy-four patients with hematological malignancies with HLA-matched (77%) and mismatched (23%) donors were analyzed in this study. Thirty-four patients (45%) were considered as high risk patients. Sixty-eight patients received standard conditioning regimens with Bu/Cy or TBI/Cy. Six patients received an intensified conditioning regimen with the addition of etoposide, thiotepa or melphalan. GVHD prophylaxis consisted of prednisolone, cyclosporine and methotrexate. Groups were matched for patient, donor, transplant characteristics and HLA compatibility. Peripheral blood stem cell collection led to the collection of a higher number of CD34+ and CD3+ cells in comparison to bone marrow collection. Leukocyte engraftment in the PBSCT group occurred in 14 days (median; range 6-26 days) and in the BMT group in 19 days (range 9-29 days; P < 0.02). The time of platelet engraftment did not differ significantly. The incidence of grades II-lV acute GVHD in the group of HLA-identical patients was 35% in the PBSCT group and 25% in the BMT group (P < 0.33, log-rank). However, there was a significant difference (P < 0.05, log-rank) in incidence and time to onset of acute GVHD II-IV comparing all patients, including the 17 mismatched transplants. Disease-free survival was 51% (19 patients) with a median of 352 days and 59% (21 patients) with a median of 760 days for PBSC and BMT transplants, respectively. In conclusion, our results indicate that allogeneic PBSCT led to significantly faster leukocyte engraftment but is associated with a higher incidence and more rapid onset of severe acute GVHD comparing all patients, including the 17 mismatched transplants. However, the incidence of severe acute GVHD in HLA-identical patients was not different between the PBSCT and BMT groups.

Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant.

We report 27 patients with relapsed acute or chronic leukemia who underwent a second hematopoietic stem cell transplant (HSCT) from a related or unrelated donor. Seventeen patients were diagnosed with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia (CML). Ages ranged from 22 to 49 years (median 37); 13 patients were female and 14 male. Relapse was diagnosed between 1 and 45 months after the first HSCT. Sixteen patients who relapsed had received an autologous transplant initially and 11 an allogeneic transplant. Ten patients relapsed within 6 months and 17 patients later than 6 months. Chemotherapy was used as reinduction for relapse after HSCT in 16 patients who had received an autologous transplant and in three who had received an allogeneic transplant, since the latter did not respond to reduction of immunosuppression to induce a graft-versus-leukemia (GVL) reaction. Five of these 19 patients (26%) achieved complete remission (CR), seven patients did not respond to chemotherapy and seven achieved a partial remission (PR). The stem cell source for the second HSCT included bone marrow (n = 12) and PBSC (n = 4) from genotypically identical unrelated donors, PBSC (n = 7) and bone marrow (n = 3) from related donors. Currently eight of the 27 patients are alive and disease-free after the second HSCT. One patient is alive and disease-free after two allogeneic transplants (day +1538), eight patients, who relapsed after an autologous transplant followed by an allogeneic transplant (days +248 to +1140), acute myeloid leukaemia (n = 6) and chronic myeloid leukemia (n = 2) are alive and disease-free. The overall disease-free survival is 30% (8/27). The overall disease-free survival of autologous transplant patients subsequently undergoing an allogeneic transplant is 43% (P = 0.049). It is suggested that a second HSCT is possible for patients with leukemia relapse following the first autologous transplant. A second transplant might also be offered to patients relapsing after the first allogeneic HSCT. Bone Marrow Transplantation (2000) 25, 41-45.

Nitric oxide synthase inhibition by L-NAME in leukocytopenic patients with severe septic shock.

OBJECTIVES: To investigate the effects of nitric oxide synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME) on hemodynamics and outcome in leukocytopenic (< 1000/microliter) patients with severe septic shock requiring strong vasopressor support. DESIGN: Prospective clinical study. SETTING: Medical intensive care unit. PATIENTS: 10 patients with hematologic malignancies in chemotherapy-induced leukocytopenia with severe septic shock and high-dose vasopressor requirement. INTERVENTION: Continuous intravenous infusion of L-NAME (0.3 mg/ kg per hour) for a study period of 24 h with prolongation for up to 96 h according to individual requirements. MEASUREMENTS AND RESULTS: Compared to baseline values, an increase in mean arterial pressure (p = 0.0021), systemic vascular resistance (p = 0.0001), and left ventricular stroke work index (p = 0.023) with a concomitant decrease in vasopressor requirement (p < 0.05) was observed during the first 24 h of L-NAME treatment. Cardiac output data were unchanged during the study period (p = 0.49). L-NAME was tapered off in five patients who again became responsive to vasopressor medication. Two patients survived the episode of septic shock and vasoactive medication was stopped. CONCLUSIONS: The data demonstrate that inhibition of nitric oxide synthase may be beneficial for the treatment of severe septic shock in leukocytopenic patients as indicated by an increase in systemic vascular resistance, mean arterial pressure, and left ventricular stroke work index.

The optimum use of intravenous immunoglobulin for prophylaxis of opportunistic infection in HIV-infected adults.

Immunoglobulin therapy is well established in the treatment of HIV-infected children with frequent bacterial infections or recurrent severe bacterial infections, and the beneficial effects are well demonstrated. Such clear recommendations regarding intravenous immunoglobulin (IVIG) therapy are currently not available for adults. Several studies have been performed in adults to determine the effects of IVIG therapy in different dosages on the frequency and severity of infections, as well as on survival. Although most studies suffer from problems in design and low patient numbers, some conclusions can be drawn. The therapy is well tolerated and does not seem to have adverse effects on patients' immune functions. Most studies demonstrate beneficial results of IVIG treatment, especially on frequency and severity of infections in patients with advanced HIV disease. However, overall survival is, if at all, only slightly prolonged. Despite the observed beneficial effects, it is unclear whether these benefits justify the high costs of continuous IVIG therapy. The role of IVIG therapy could be further altered by the recent improvements in antiviral drug therapy. Taken together, the available data suggest an individualised usage of IVIG as adjunctive therapy in adults with advanced HIV infection and severe or recurrent bacterial infections.

Chronic eosinophilic leukemia: successful treatment with an unrelated bone marrow transplantation.

The optimal treatment of eosinophilic leukemia is still uncertain. We report the successful treatment of a 21-year-old patient with eosinophilic leukemia, without cytogenetic abnormalities, by bone marrow transplantation from an unrelated donor. The conditioning regimen for the transplantation consisted of fractionated total body irradiation and cyclophosphamide. Acute GVHD, grade I, post-transplantation was successfully treated. No other severe complications occured. The patient is alive in complete remission 21 months after unrelated bone marrow transplantation.

Mycophenolate mofetil in stem cell transplant patients in relation to plasma level of active metabolite.

OBJECTIVES: To investigate mycophenolate mofetil (MMF) plasma levels and impact on acute graft versus host disease (aGvHD) after stem cell transplantation (SCT). METHODS: SCT patients (n = 14) with aGvHD (>/= II) receiving MMF (1-3 g/d) in addition to cyclosporine, prednisolone, and methotrexate for aGvHD prophylaxis were investigated. Plasma levels of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were determined by high-performance liquid chromatography. RESULTS: Overall median steady state pre-dose plasma MPA concentration was 0.47 mg/L and increased within 75 min after administration to 1.64 mg/L. In comparison to patients with skin aGvHD, patients with gut aGvHD had lower MPA concentrations, both pre-dose (p = 0.16) and after 75 min, (p = 0.02). All 7 patients with skin aGvHD but only 2 patients with gut aGvHD responded to MMF. Overall, the pre-dose plasma MPA concentration was significantly (p = 0.007) greater in responders (n = 9) than in non-responders (n = 5). CONCLUSION: MMF seems to be an effective treatment for aGvHD in SCT patients particular in those patients without gut involvement.

Tyrosine phosphorylation in peripheral T cells of kidney transplant recipients: analyses of baseline levels and response to T cell receptor stimulation.

Impaired immunosurveillance in recipients of organ transplants has been attributed to alleviation of T cell functions. We analyzed the phosphorylation of tyrosine residues in T cells of peripheral blood, and after T cell receptor (TCR) stimulation. The TCR was stimulated by OKT3 monoclonal antibody (mAb) in non-separated heparinized blood specimens of patients (n=64) and healthy controls (n=25). After fixation and red cell lysis, lymphocytes were permeabilized by saponin. Subsequently, intracellular phosphotyrosine residues and surface CD3 antigen were stained simultaneously with specific mAbs. We analyzed transplant recipients and healthy donors for baseline levels of total cellular tyrosine phosphorylation and for increase in phosphotyrosine content following stimulation by OKT3. Phosphotyrosine levels were significantly lower in non-stimulated T cells of kidney transplant recipients compared to controls (p=0.004). There was a marked variability in the levels of tyrosine phosphorylation among transplanted patients (p=0.02). T cell receptor stimulation by OKT3 mAb in vitro led to a strong increase of tyrosine phosphorylation in all specimens of patients and healthy controls. In conclusion, we demonstrated decreased phosphotyrosine levels in T cells of kidney transplant recipients compared to healthy donors. However, increase in tyrosine phosphorylation was not impaired in all patients as a result of TCR stimulation.

Lovastatin induces p21WAF1/Cip1 in human vascular smooth muscle cells: influence on protein phosphorylation, cell cycle, induction of apoptosis, and growth inhibition.

Morbidity, mortality and the incidence of myocardial revascularisation procedures can be reduced by simvastatin, an inhibitor of the HMG-CoA reductase (EC 1.1.1.34). It was hypothesised that inhibition of isoprenylation of signalling proteins by HMG-CoA reductase inhibitors (vastatins), especially of the p21ras proteins could be causative for suppression of vascular smooth muscle cell (SMC) proliferation. The primary pharmacological mechanism of vastatins on human vascular SMC still remains unexplained. To analyse the influence of vastatins, SMC grown in presence of endothelial cell growth supplement (ECGS) were exposed to different concentrations of lovastatin. At 10 microM concentration, inhibition of SMC proliferation was associated with induction of apoptosis in a large fraction of cells as at the 1 microM level apoptosis was induced only in a minority of SMC. Protein phosphorylation on tyrosine, serine and threonine residues demonstrated no differences to untreated controls. Lovastatin induced arrest of cells in G0/G1 phase of the cell cycle and DNA synthesis was reduced. Western blot analysis demonstrated a significant induction of p21WAF1/Cip1 protein expression. This led to strong inhibition of cyclin dependent kinases (cdks) resulting in a cell cycle arrest. Our study provides evidence for a pharmacological explanation for the inhibition of ECGS-driven proliferation of human SMC by lovastatin.