Change of colloidal and surface properties of Mytilus edulis foot protein 1 in the presence of an oxidation (NaIO4) or a complex-binding (Cu2+) agent.

Quartz crystal microbalance with dissipation monitoring (QCM-D) was used to study the viscoelastic properties of the blue mussel, Mytilus edulis, foot protein 1 (Mefp-1) adsorbed on modified hydrophobic gold surfaces. The change in viscoelasticity was studied after addition of Cu2+ and Mn2+, which theoretically could induce metal complex formation with 3,4-dihydroxyphenylalanine (DOPA) moieties. We also used NaIO4, a nonmetal oxidative agent known to induce di-DOPA formation. Reduction in viscoelasticity of adsorbed Mefp-1 followed the order of NaIO4 > Cu2+ > buffer control > Mn2+. We also studied the formation of molecular aggregates of Mefp-1 in solution with the use of dynamic light scattering (DLS). We found that addition of Cu2+, but not Mn2+, induced the formation of larger DLS-detectable aggregates. Minor aggregate formation was found with NaIO4. With the analytical resolution of small angle X-ray scattering (SAXS), we could detect differences in the molecular structure between NaIO4- and Cu2+-treated Mefp-1 aggregates. We concluded from this study that Cu2+ could participate in intermolecular cross-linking of the Mefp-1 molecule via metal complex formation. Metal incorporation in the protein most likely increases the abrasion resistance of the Mefp-1 layer. NaIO4, on the other hand, resulted in mainly intramolecular formation of di-DOPA, but failed to induce larger intermolecular aggregation phenomena. The described methodological combination of surface sensitive methods, like QCM-D, and bulk sensitive methods, like DLS and SAXS, generates high resolution results and is an attractive platform to investigate intra- and intermolecular aspects of assembly and cross-linking of the Mefp proteins.

Realtime photoacoustic microscopy of murine cardiovascular dynamics.

Non-invasive visualization of cardiovascular dynamics in small animals is challenging due to their rapid heart-rates. We present a realtime photoacoustic imaging system consisting of a 30-MHz ultrasound array transducer, receive electronics, a high-repetition-rate laser, and a multicore-computer, and demonstrate its ability to image optically-absorbing structures of the beating hearts of young athymic nude mice at rates of approximately 50 frames per second with 100 microm x 25 microm spatial resolution. To our knowledge this is the first report of realtime photoacoustic imaging of physiological dynamics.

Pharmacologic variables associated with the development of neurologic toxicity in patients treated with suramin.

PURPOSE: To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin. METHODS: Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 micrograms/mL) for a fixed duration (2 to 8 weeks). RESULTS: Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-micrograms/mL concentration. One patient treated at the 215-micrograms/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. Pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 micrograms/mL, and area under the curve (AUC) greater than 200 micrograms/mL. CONCLUSION: Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 micrograms/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to < or = 157 mg/kg given over a period of > or = 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 micrograms/mL to < or = 25 days, and limit the AUC greater than 200 micrograms/mL to < or = 48,000 mg.h/AL.

Leukemia after a small dose of radioiodine for metastatic thyroid cancer.

Radioiodine is widely used in the treatment of thyroid cancer. It is one of the most benign forms of therapy for malignancy. Leukemia is a rare complication of 131I therapy, usually occurring after cumulative dosages of more than 800 mCi and with intervals between doses of less than 12 months. We report the occurrence of acute myelogenous leukemia in a 28-yr-old woman 14 months after receiving a total dose of 300 mCi 131I for metastatic follicular thyroid cancer. We also review the published literature of the incidence of leukemia after low dose 131I.

A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone.

Gallium nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day gallium nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross-links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of gallium nitrate is safe and effective for treating patients with advanced Paget's disease of bone.

Development of Nelson's syndrome in a patient with recurrent Cushing's disease. Analysis of secretory behavior of the pituitary tumor.

A markedly cushingoid 32-year-old man presented to Queens Hospital Center with headache, hyperpigmentation, and visual field loss. Twelve years earlier, he had undergone subtotal adrenalectomy for Cushing's disease, but symptoms of hypercortisolemia promptly recurred. Workup revealed the presence of a large, expanding intrasellar mass, plasma ACTH levels between 3,000 and 10,000 pg/ml, and markedly elevated cortisol levels. The secretion of ACTH (mainly ACTH 1-39-like peptide) by the pituitary tumor showed neither diurnal periodicity nor response to a variety of pharmacologic agents known to affect ACTH secretion. The patient demonstrates a rarely observed presentation of Nelson's syndrome, with aggressive adrenotropic pituitary tumor growth even in the presence of chronic hypercortisolemia.

Immune modulation in autologous bone marrow transplantation: cyclosporine and gamma-interferon trial.

From March 1994 to November 1994, 16 patients with high risk hematological malignancies were entered in a phase I clinical trial, designed to confirm the toxicity of cyclosporine and gamma interferon given to induce autologous graft-versus-host disease (GVHD) after autologous bone marrow transplantation (ABMT). This trial was based on the results in a rodent model, in which cyclosporine given after ABMT induces an autoimmune syndrome (autologous GVHD) identical to allogeneic GVHD. Further, this autologous GVHD is associated with a graft-versus-tumor effect augmented by interferon that upregulates MHC class II expression on normal and tumor cells, the target of the cytolytic T cells in autologous GVHD. In this trial, cyclosporine 1 mg/kg/day was given from the day of bone marrow reinfusion until the completion of the interferon and gamma-interferon. Gamma-interferon at 0.025 mg/m2 every other day was started when the total white cell count was >200 cells/ml for 2 consecutive days and continued for a total of 10 doses after ABMT. The preparative regimens were busulfan and cyclophosphamide, or cyclophosphamide with total body irradiation. All patients received 4HC-purged marrow grafts. Median age was 45 years (range 19-68). The diagnoses included chemo-resistant non-Hodgkin's lymphoma (10), acute lymphoblastic leukemia (two), chemo-resistant Hodgkin's disease (two), acute myeloid leukemia (one), and multiple myeloma (one). Median absolute neutrophil count recovery was 25.5 days (range 19-46 days). Median platelet count recovery was 40.5 days (range 28-279 days). There were nine deaths, two were related to transplant toxicity (infection), while the other seven were due to relapse. Event-free survival with a median of 964 days (range 19-1441 days of follow-up was 44%. In conclusion, treatment with cyclosporine, and gamma-interferon after ABMT was well tolerated and did not impair engraftment. Further studies with a larger number of patients are required to document any beneficial anti-tumor effect of autologous GVHD induction after ABMT.

A preliminary risk-benefit assessment of paclitaxel.

Paclitaxel is an antineoplastic agent, first isolated and described in 1971. Despite its novel structure and apparent activity in vitro, little interest was shown in developing the compound because of its scarcity, problems with its formulation and the mistaken assumption that its mechanism of action was similar to that of the vinca alkaloids. Approximately 10 years later, the unique mechanism of action of paclitaxel, its ability to stabilise microtubules, was discovered, and its activity against human tumour xenografts was demonstrated. Interest in the drug was reignited and clinical testing began. Severe hypersensitivity reactions were controlled in the phase II programme with a premedication regimen consisting of dexamethasone, histamine H1-antagonists and H2-antagonists. Neutropenia was dose limiting in all studies conducted in patients with solid tumours. This toxicity was schedule-dependent, and less severe when paclitaxel was administered as a 3-hour infusion regimen. Peripheral neuropathy was mild to moderate in the initial experience, and dose-dependent. However, when bone marrow support with haemopoietic growth factors was used to allow paclitaxel dose intensification, neurotoxicity became dose limiting. To date, substantial clinical efficacy has been demonstrated in ovarian, breast, non-small-cell lung, and head and neck cancers. Response rates were low in initial studies in melanoma, prostate, colon, cervix and renal cancer. In December 1992, US Food and Drug Administration approval was granted for the use of paclitaxel as second-line therapy in ovarian cancer patients. More recently, similar approval was granted for use in recurrent breast cancer. Nevertheless, important questions remain.(ABSTRACT TRUNCATED AT 250 WORDS)

A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer: toxicity and response.

INTRODUCTION: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. OBJECTIVE: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 microg/ml. METHODS: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 microg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. RESULTS: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 microg/ml for 4 or more weeks. A single patient treated at 215 microg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 microg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 microg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. CONCLUSIONS: In summary, although plasma suramin concentrations were maintained below 300 microg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 microg/ml for 4 or more weeks. Therapy at 215 and 175 microg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin's activity in hormone-refractory prostate cancer.

Transient headache and impaired vision after intravenous thyrotropin-releasing hormone in a patient with pituitary macroadenoma.

We report a case of transient headache and impaired vision following administration of intravenous thyrotropin-releasing hormone (TRH) to a woman with a non-functioning pituitary macroadenoma, visual field defect, and elevated thyroid-stimulating hormone (TSH). The symptoms lasted for two hours and then resolved without known sequelae. There are a few other reported cases of similar adverse reactions to neuroendocrine manipulation in patients with pituitary macroadenomas. This is the second reported case of such adverse reactions to TRH alone and the first in which the patient had prior elevation of TSH.

Role of thyroid-stimulating immunoglobulin in aggressiveness of well-differentiated thyroid cancer.

OBJECTIVE: To assess whether a relationship exists between thyroid-stimulating antibodies and increased aggressiveness of thyroid cancer. METHODS: We analyzed clinical, histologic, and biochemical data, including thyroid-stimulating antibodies, from 26 patients (24 women and 2 men) who had had well-differentiated thyroid carcinoma for 1 to 5 years and had undergone total thyroidectomy and radioactive iodine ablative therapy. For analysis, the overall study cohort was divided into two groups: group 1 (N = 16), with stable disease and no evidence of metastatic activity, and group 2 (N = 10), with aggressive disease and substantiated metastatic involvement. RESULTS: The thyroid-stimulating antibodies ranged from 92 to 129% in group 1 and from 95 to 118% in group 2. Thus, both study groups had thyroid-stimulating antibody levels within the normal range (normal, <130%). CONCLUSIONS: Apparently, thyroid-stimulating antibodies had no contributory role in the growth of the metastatic lesions in the 10 patients with aggressive disease. Further studies should be undertaken to investigate other potential factors involved in stimulating the progression of thyroid cancer.

Papillary carcinoma of the thyroid with manifestations resembling Graves' disease.

OBJECTIVE: To describe a case of papillary carcinoma of the thyroid that mimicked a diffuse toxic goiter. METHODS: We present a detailed case report, review related cases in the literature, and discuss the possible role of autoantibodies in promoting the growth of papillary thyroid tumor. RESULTS: A 28-year-old woman had a 6-month history of weight loss, palpitations, increased anxiety, and enlargement of her thyroid gland. Laboratory studies confirmed the presence of hyperthyroidism. A 1-cm nodule was identified at the left upper pole of the thyroid. Fine-needle aspiration biopsy of this nodule revealed papillary carcinoma of the thyroid. Total thyroidectomy and a modified radical neck dissection were performed. Microscopic examination showed that the entire gland was replaced by a papillary carcinoma with a predominantly follicular pattern of growth. Of 44 lymph nodes tested, 31 were positive for metastatic papillary thyroid carcinoma. The presence of thyroid antibodies may have had a role in the aggressiveness of the patient's disease. CONCLUSION: To our knowledge, this is the first published report of a papillary thyroid cancer with manifestations resembling Graves' disease.

The course of lymphocytic hypophysitis.

A 27-year-old woman presented to our institution in her seventh month of pregnancy with complaints of headache and visual field disturbance. Workup revealed bitemporal hemianopia, a markedly enlarged pituitary gland on computed tomography scan, and biochemical evidence of partial hypopituitarism. At surgery, a biopsy specimen of the pituitary gland was taken revealing lymphocytic hypophysitis. The patient was treated with steroids and replacement doses of thyroid hormone. Visual fields improved postoperatively. A repeat computed tomography scan obtained 2 months after an uneventful pregnancy showed that her pituitary had regained normal size and contour. Over the next 9 months she had gradual recovery of all pituitary function. This case allowed us to follow and document the course of lymphocytic hypophysitis from its presentation as a macroadenoma with partial hypopituitarism to full recovery of both size and hormonal function of the pituitary. Lymphocytic hypophysitis should be considered in the differential diagnosis of a pituitary mass or pituitary dysfunction presenting in pregnancy. In patients with suspected lymphocytic hypophysitis and a pituitary mass, a trial of steroids may be therapeutic.

[Clinical imaging in psychiatry]. / Imagerie médicale en psychiatrie.

Brain imaging has made surprisingly remarkable progress since the early, and now historic days, of invasive radiology, which has now been replaced with a number of spectacularly precise techniques: structural (CT Scan, MRI) and functional (PET, SPECT) imaging, direct imaging during neurosurgery, EEG and its computer-assisted derivatives, and transcerebral ultrasonography. We present five cases with two alleged autisms, a cerebral malaria, a panic disorder and to Parkinson disease with a depressive component. Using modern imaging methods the following respective diagnoses were arrived at: a left temporal cyst, a Sanfilippo mucopolysaccharidosis, a septum lucidum agenesis, a right temporal cyst, and a pituitary adenoma. These cases illustrate the scientific, emotional and philosophical impact, on physicians, and patients alike, of modern imaging technology. Neuroradiology, biochemistry and surgical imaging require a multi disciplinary approach and a perfect knowledge of psychiatric semeiology. In addition, they stimulate us to carefully reassess our sociocultural understanding to mental illness.

[Panic attacks and 24-hour ambulatory EEG monitoring]. / Attaques de panique et EEG ambulatoire de 24 heures.

A 24 hour ambulatory EEG study performed in a population of 300 non epileptic outpatients with an anxious and depressive pathology revealed a high prevalence of abnormalities in subjects referred with panic disorder. Two groups of 150 medication-free patients each have been selected on the base of DSM-III-R = one with panic attacks (PA), the other with depressive patients without paroxystic anxiety (DS). The results showed respectively = in the PA group 63.2% abnormal, 19.7% normal and 17.1% dubious records. In the DS group = 74.5% normal, 18.3% abnormal and 7.2% dubious records. Epileptiform abnormalities were 4 times more frequent in the PA group (80%) than in the DS group (20%). Two nycthemeral peaks were found (5-8 pm and 3 hours after awakening). MRI has permitted the discovery of abnormal cerebral images in 3 patients of the PA group (cyst of the insula, temporal and parietal cryptic angiomas, sequelae of a parietal vasculo-cerebral stroke) frequency appearing to be clearly superior to the one resulting from recent epidemiologic data. The subclinical character of 2/3 of these abnormalities refers beyond epilepsy to their signification in the field of emotive and intellectual disturbances. The paradoxal efficiency of tricyclic drugs in panic disorder, sets the problem of their eventual antiepileptic action at low doses. If recent data on standard EEG in panic disorder is available, we did not find any similar study to ours in order to confront our results.

Paclitaxel dose intensity.

Paclitaxel is effective in the treatment of cancer of the ovary and cancer of the breast, as well as other malignancies. We have analyzed available phase II data in these two diseases, to assess the possibility that paclitaxel dose intensity may be important in the induction of disease response. When analyzed by the methods developed by Hrynuik and Levin, available data suggest that the relationship between objective disease response and paclitaxel dose intensity in recurrent cancer of the ovary is strongly statistically significant with a two-sided p value of 0.022. Available data suggest that the relationship in breast cancer is even stronger, with a two-sided p value of 0.004. In both diseases, optimal results have been observed at the dose schedule of 250 mg/m2/21 days, given as a 24 hour IV infusion. We have also performed an analysis comparing the only two prospective randomized studies that examined the potential role of dose intensity for this drug in cancer of the ovary. At 135 mg/m2/21 days, the objective response rate was 13.2%; and at 250 mg/m2/21 days, the objective response rate was 35.9%. The response rate seen at the intermediate dose of 175 were intermediate to 135 and 250; and linear regression analysis shows a correlation coefficient for these data of 0.946. Since flexible cytokine support may be essential in maintaining paclitaxel dose intensity, we have also discussed this approach as well as the paclitaxel dosing strategy that is associated with optimal clinical results in recurrent cancer of the ovary.

Acute bleeding after bone marrow transplantation (BMT)- incidence and effect on survival. A quantitative analysis in 1,402 patients.

Acute bleeding after bone marrow transplantation (BMT) was investigated in 1,402 patients receiving transplants at Johns Hopkins Hospital between January 1, 1986 and June 30, 1995. Bleeding categorization was based on daily scores of intensity used by the blood transfusion service. Moderate and severe episodes were analyzed for bleeding sites. Analysis of the cause of death and the interval of the bleeding episode to outcome endpoints was recorded. Survival estimates were computed for 1,353 BMT patients. The overall incidence was 34%. Minor bleeding was seen in 10.6%, moderate bleeding was seen in 11.3%, and severe bleeding was seen in 12% of all patients. Fourteen percent of patients had moderate or severe gastrointestinal hemorrhage, 6.4% had moderate or severe hemorrhagic cystitis, 2.8% had pulmonary hemorrhage, and 2% had intracranial hemorrhage. Sixty-one percent had 1 bleeding site and 34.4% had more than 1 site. Moderate and severe bleeding was more prevalent in allogeneic (31%) and unrelated patients (62.5%) compared with autologous patients (18.5%). Significant distribution of incidence was found among the different diagnoses, but not by disease status in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma. Bleeding was associated with significantly reduced survival in allogeneic, autologous, and unrelated BMT and in each disease category except multiple myeloma. Survival was correlated with the bleeding intensity, bleeding site, and the number of sites. Although close temporal association was evident to mortality, bleeding was recorded as the cause of death in only the minority of cases compared with other toxicities after BMT (graft-versus-host disease, infections, and preparative regimen toxicity). Acute bleeding is a common complication after BMT that is profoundly associated with morbidity and mortality. Although bleeding was not a direct cause of death in the majority of cases, it has a potential prognostic implication as a predictor of poor outcome in clinical assessment of patients after BMT.

p185erbB2 binds to GRP94 in vivo. Dissociation of the p185erbB2/GRP94 heterocomplex by benzoquinone ansamycins precedes depletion of p185erbB2.

Treatment of SKBr3 cells with benzoquinone ansamycins, such as geldanamycin (GA), depletes p185erbB2, the receptor tyrosine kinase encoded by the erbB2 gene. In the same cells, a biologically active benzoquinone photoaffinity label specifically binds a protein of about 100 kDa, and the ability of various GA derivatives to reduce the intracellular level of p185erbB2 correlates with their ability to compete with the photoaffinity label for binding to this protein. In this report, we present evidence that the approximately 100-kDa ansamycin-binding protein is GRP94. Membrane-associated p185erbB2 exists in a stable complex with GRP94. GA binding to GRP94 disrupts this complex, leading to degradation of pre-existing p185erbB2 protein, and resulting in an altered subcellular distribution of newly synthesized p185erbB2.

A phase I study of pentosan polysulfate sodium in patients with advanced malignancies.

BACKGROUND: Pentosan polysulfate (xylanopolyhydrogensulfate) is a semi-synthetic sulfated heparinoid polysaccharide which has been used as an anticoagulant for nearly thirty years in Europe. It antagonizes the binding of bFGF to cell surface receptors and has thus been evaluated for antitumor activity in several animal models and human tumor cell lines. In two angiogenic models pentosan has been shown to inhibit bFGF stimulation of angiogenesis. Previous clinical studies have determined the coagulation effects of pentosan to be the dose-limiting toxicity. PATIENTS AND METHODS: We conducted a phase I study designed to define the duration-limiting toxicity associated with progressive prolongation of a continuous intravenous infusion (three, five, and eight weeks). This study was not designed to escalate the dose of pentosan beyond that required to maintain the activated partial thromboplastin time (aPTT) between 1.8 and 2.2 times the baseline value. RESULTS: Thirteen patients with advanced stage metastatic cancer were enrolled (median age 50 years, range 34 to 61 years). Four patients were treated in cohort #1 (three weeks of infusional therapy), five patients were treated in cohort #2 (five weeks of therapy), and four patients in cohort #3 (eight weeks of therapy). All patients experienced a progressive prolongation of their aPTT and PT. Furthermore, all patients experienced at least grade I thrombocytopenia. Other complications were, in general, mild. One patient developed grade III liver abnormalities while receiving the eight-week infusion and another patient developed grade IV thrombocytopenia while receiving the same regimen. One patient with colon cancer had stable disease for 24 weeks, while the remaining 12 patients had no objective evidence of response. CONCLUSION: Pentosan was well tolerated when doses were adjusted for aPTT prolongations and a five-week cycle appeared to be the maximum tolerated duration of infusion (initially 4 mg/kg/day). One patient had stable disease, but there was no objective tumor response noted in the remaining 12 patients.