Continuous infusion of the anti-CD22 immunotoxin IgG-RFB4-SMPT-dgA in patients with B-cell lymphoma: a phase I study

IgG-RFB4-SMPT-dgA consists of deglycosylated ricin A chain (dgA) coupled to the monoclonal antihuman CD22 antibody, RFB4. This study determined the maximally tolerated dose (MTD) of this immunotoxin (IT) administered as a continuous 8-day infusion to 18 patients with B-cell lymphoma (30% CD22+ tumor cells) over 8 days. The MTD was 19.2 mg/m2/192 h (maximum toxicity grade 1), with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT) at 28.8 mg/m2/192 h (grades 3 through 5 in 7 of 11 patients). Predictors of severe VLS included serum IT concentrations greater than 1,000 ng/mL and the absence of circulating tumor cells. Decreased urine sodium excreted in 24 hours provided evidence for mild VLS without notable changes in serum albumin. Four partial responses, 3 minor responses, 6 stable disease, and 3 progression of disease were observed. The mean maximal serum concentration (Cmax) in initial courses at the MTD (19.2 mg/m2) was 443 +/- 144 ng/mL (n = 3; range, 326 to 604). At 28.8 mg/m2/192 h, the Cmax was highly variable (n = 11; mean, 1,102 +/- 702; range, 9.6 to 2,032 ng/mL). Human antimouse or antiricin antibodies developed in 6 of 16 (37.5%) patients after one course of IT. However, 10 eligible patients received multiple courses of IT. Changes in serum cytokines and cytokine receptors did not correlate with toxicity but decreased soluble interleukin-2 receptor concentrations correlated with clinical response. Comparison to a prior study with the same IT administered by intermittent bolus infusions (Amlot et al, Blood 82:2624, 1993) suggests similar clinical response, toxicity, and immunogenicity.     

Ureteral jets in healthy subjects and in patients with unilateral ureteral calculi: comparison with color Doppler US

Color Doppler ultrasound was used to image the ureteral jets in 17 healthy subjects and 26 patients with ureteral calculi proved with intravenous urography. In patients with ureteral calculi, three patterns of ureteral jets were seen: no detectable urine flow from the symptomatic side (12 patients), low-level continuous flow from the symptomatic side (four patients), and periodic ureteral jets on the symptomatic side that were not significantly different from ureteral jets of healthy subjects (10 patients). Of the 12 patients with high-grade obstruction on urograms, 11 had ureteral jets significantly different from those of healthy subjects (either no detectable ureteral jets or continuous low-level jets on the symptomatic side). Only three of the 11 patients with low-grade obstruction or nonobstructing stones had ureteral jets that were different from those of healthy subjects. It is concluded that analysis of ureteral jets with color Doppler can enable detection and qualitative determination of the degree of ureteral obstruction in many patients with unilateral ureteral calculi.     

Bone mineral content in early-postmenopausal and postmenopausal osteoporotic women: comparison of measurement methods

To investigate associations among methods for noninvasive measurement of skeletal bone mass, we studied 40 healthy early postmenopausal women and 68 older postmenopausal women with osteoporosis. Methods included single- and dual-energy quantitative computed tomography (QCT) and dual-photon absorptiometry (DPA) of the lumbar spine, single-photon absorptiometry (SPA) of the distal third of the radius, and combined cortical thickness (CCT) of the second metacarpal shaft. Lateral thoracolumbar radiography was performed, and a spinal fracture index was calculated. There was good correlation between QCT and DPA methods in early postmenopausal women and modest correlation in postmenopausal osteoporotic women. Correlations between spinal measurements (QCT or DPA) and appendicular cortical measurements (SPA or CCT) were modest in healthy women and poor in osteoporotic women. Measurements resulting from one method are not predictive of those by another method for the individual patient. The strongest correlation with severity of vertebral fracture is provided by QCT; the weakest, by SPA. There was a high correlation between single- and dual-energy QCT results, indicating that errors due to vertebral fat are not substantial in these postmenopausal women. Single-energy QCT may be adequate and perhaps preferable for assessing postmenopausal women. The measurement of spinal trabecular bone density by QCT discriminates between osteoporotic women and younger healthy women with more sensitivity than measurements of spinal integral bone by DPA or of appendicular cortical bone by SPA or CCT.     

Intravenous DSA examination of patients with suspected cerebral ischemia

We analyzed the role of intravenous digital subtraction angiography (DSA), with neck and intracranial views as a definitive pretherapy study, in patients who had symptomatic cerebral ischemia. Eighty-six patients, 25 of whom had subsequent carotid thromboendarterectomy, were examined. An adequate pretherapy intravenous DSA study allowed us to define each carotid bifurcation as either normal, having insignificant stenosis, or having significant stenosis, and the examination excluded significant tandem stenosis in the intracranial internal carotid arteries. Adequate pretherapy intravenous DSA studies were obtained in 73% of patients, including 50% of those in the presurgical group. Selective carotid arteriography was not required in these patients. Inadequate presurgical studies were predominantly due to plaque misregistration, inadequate projection, and superimposition that obscured the proximal internal carotid arteries. Selective carotid arteriography was performed in these patients prior to surgery. Inadequate studies prior to initiation of medical therapy were predominantly due to soft tissue misregistration artifact, and superimposition. Intravenous DSA is a valuable screening test and can be used to guide therapy in the majority of patients who have symptomatic cerebral ischemia.     

Focal hepatic masses and fatty infiltration detected by enhanced dynamic CT

A prospective evaluation of 185 consecutive patients with abdominal pain or suspected hepatic malignancy was performed to compare the diagnostic accuracy of contrast material-enhanced incremental dynamic computed tomography (IDCT) scans with plain CT scans for detection of hepatic masses and fatty infiltration of the liver. After a series of nondynamic plain CT scans, patients were examined at 7.5 scans/min during intravenous injection of 50 g of iodinated contrast material. Enhanced IDCT study was found to be an accurate, reproducible technique for liver evaluation. Of 155 neoplasms measured in 59 patients, liver-to-lesion differences of less than 10 HU were seen in only two tumors in IDCT scans as compared with 31 in plain CT scans. These differences were not significantly affected by lesion size for neoplasms greater than 6 mm in diameter. A confident diagnosis of fatty infiltration (23 patients) could be made when the spleen-minus-liver difference was 25 HU on enhanced IDCT scans and 10 HU on plain CT scans. In eight patients with liver metastases, there was little variation in the attenuation values of normal-appearing liver between serial examination studies (8 HU average).     

Cloning, mapping and RNA analysis of the human methionine synthase gene

Elevated levels of plasma homocysteine is a risk factor in both birth defects and vascular disease. Methionine synthase (MS) is a cobalamin dependent enzyme which catalyzes methylation of homocysteine to methionine. Impaired MS activity is expected to lead to increased levels of plasma homocysteine. In addition, defects in this gene may underlie the methionine-dependence observed in a number of human tumor cell lines. We describe here the isolation and characterization of the human MS cDNA. It contains an open reading frame of 3798 nucleotides encoding a protein of 1265 amino acids with a predicted molecular mass of 140 kDa. The amino acid sequence of the human MS is 55% identical with that of the Escherichia coli enzyme (METH) and 64% identical with the predicted Caenorhabditis elegans enzyme. Seven peptide sequences derived from purified porcine MS have substantial similarity to the human protein. Northern analysis indicates that the MS RNA is present in a wide variety of tissues. We have mapped the human gene to chromosomal location 1q43, a region found monosomic in individuals with deletion 1q syndrome. The isolation of the MS cDNA will now allow the direct determination of whether mutations in this gene contribute to folate-related neural tube defects, cardiovascular diseases, and birth defects.