Second marrow transplants in patients with aplastic anemia rejecting the first graft: use of a conditioning regimen including cyclophosphamide and antithymocyte globulin

Sixteen (11%) of 146 consecutive patients with severe aplastic anemia prepared for engraftment with cyclophosphamide (200 mg/kg) rejected marrow grafts from their HLA-identical siblings. They were given a second marrow transplant from either the same (n = 13) or a second (n = 3) HLA-identical sibling between 23 and 743 (median 86) days after the first transplant. The preparation for the second transplant included cyclophosphamide, 50 mg/kg, on each of four successive days. Twelve hours after each of the first three doses of cyclophosphamide, antithymocyte globulin, 30 mg/kg/dose, was infused. One of the 16 patients died from infection too early after the second transplant to be evaluated, two had failure of engraftment and died with infection, one rejected the second graft and is surviving almost 5 years later with full autologous marrow recovery, and 12 had successful and sustained second grafts. Of these 12, six are surviving between 11 months and 7 3/4 years. Four of the six have no graft-v-host disease (GVHD), while two have chronic GVHD requiring treatment. Five have Karnofsky scores of 100% and one of 90%. Six of the 12 patients with sustained grafts died between 63 days and 38 months after transplantation, four with infections (related in two patients to chronic GVHD), one with acute GVHD, and one with hemorrhage. The average interval from first to second transplant was 308 days during the past five years, compared to 61 days in earlier patients. Five of seven recent patients are surviving, compared to two of nine earlier patients. In conclusion, successful second transplants after cyclophosphamide and antithymocyte globulin are possible in most patients with aplastic anemia who have rejected their first marrow grafts; however, mortality remains high, with only 40% of the patients becoming long-term survivors.     

Interleukin-4 enhances the survival of severe combined immunodeficient mice engrafted with human B-cell precursor leukemia

Human interleukin-4 (huIL-4) has been shown to inhibit the growth in vitro of cells from patients with acute lymphoblastic leukemia (ALL). With the aim of determining whether this cytokine might be useful in the treatment of patients with ALL, the effects of huIL-4 on human B- cell precursor ALL engrafted in severe combined immunodeficient (SCID) mice were examined. The inhibition of [3H] thymidine uptake of primary ALL cells by huIL-4 was maintained following engraftment and passage of leukemia in SCID mice. Five of seven xenograft leukemias showed significant inhibition in vitro by huIL-4 at concentrations as low as 0.5 ng/mL; furthermore, huIL-4 counteracted the proliferative effects of IL-7. When used to treat two human leukemias engrafted in SCID mice, huIL-4 200 microgram/kg/d, as a continuous 14-day subcutaneous infusion, suppressed the appearance of circulating lymphoblasts and extended survival of mice by 39% and 108%, respectively, the first demonstration of IL-4 activity against human leukemia in vivo. The mean steady-state huIL-4 level in mouse plasma during the infusion was 1.46 ng/mL (SEM +/- 0.14 ng/mL), which was similar to concentrations found to be effective in vitro. ALL cells obtained from mice relapsing after huIL-4 treatment continued to show inhibition by the cytokine in vitro. These data suggest that IL-4 may be useful in the treatment of patients with ALL.     

Insulin and blood pressure responses to changes in salt intake

In this study we evaluated the role of insulin in hypertension and on salt sensitivity. The study was conducted in 47 consecutive patients attending the Center for the Detection and Treatment of Cardiovascular and Metabolic Risk factors. The relationships between fasting and post-glucose load insulin levels and the blood pressure (BP) responses to changes in salt intake, were investigated. No correlation was observed between fasting or 2-h post-load insulin levels and mean BP (MBP), systolic BP (SBP) or diastolic BP (DBP). The plasma concentrations of insulin were not significantly related to body mass index (BMI) (r2 = 0.05; P = 0.135). Neither fasting nor 2-h post-load insulin predicted the BP response to changes in salt intake. A reduction in salt intake from 316 +/- 13 to 26 PM 3 mmoles/day, produced similar BP lowering in subjects with fasting insulin >15 microU/ml and in subjects with normal fasting insulin levels (<15 microU/ml). In addition, no relationship was observed between the magnitude of the BP responses to salt and the levels of insulin, either fasting (r2 = 0.007; P = 0.86) or 2-h after a glucose load (r2 = 0.01; P = 0.213). A very strong association was found between body weight or BMI and MBP (r2 = 0.443; P< 0.0001). In conclusion, our results are against the view of a cause-effect relationship between insulin and BP levels. In addition, the insulin status of a patient does not predict (nor determines) his (her) vascular reactivity to changes in salt intake. Finally, our findings further support the existence of a strong and direct association between body weight and hypertension, and speak against a major role of insulin in the pathogenesis of hypertension associated with obesity.     

Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies [published erratum appears in Blood 1996 Oct 1;88(7):2818]

Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.     

Impact of the diagnostic procedure on outcome measures of swallowing rehabilitation in head and neck cancer patients

This study was designed to determine whether swallow rehabilitation outcomes were affected by the type of evaluation procedure utilized by the clinician. The two evaluation techniques compared were the bedside examination and videofluoroscopy (the modified barium swallow). Ten institutions participated in this study, enrolling a total of 103 partial laryngectomized patients, 21 in the bedside arm and 82 in the videofluoroscopy arm. Data on recovery of oral intake were collected weekly. All patients received an X-ray study of swallow at 3 months after the operation. Mean time to oral intake of food was significantly lower in patients assessed with bedside examination. Overall swallow measures of transit times and swallow efficiencies after 3 months revealed significantly better function in the videofluoroscopy group. Results are discussed in terms of the visibility of swallow physiology with the two assessment techniques, the accuracy of therapy planning with the bedside examination versus videofluoroscopy and the ability of head and neck cancer patients to tolerate some aspiration without developing aspiration pneumonia. This research was funded by NIH grant PO1 CA40007     

Postthaw stability of fibrinogen in cryoprecipitate stored between 1 and 6 degrees C

The fibrinogen activity in thawed cryoprecipitate stored between 1 and 6 degrees C is maintained essentially unchanged in most bags for a month. Occasionally, a bag will have a reduction in fibrinogen. If pooling has not occurred, thawed cryoprecipitate should be useful as a source of fibrinogen for a period of time considerably in excess of the 6 hours allowed for its use as a source of factor VIII or von Willebrand factor.     

In vitro and in vivo selectin-blocking activities of sulfated lipids and sulfated sialyl compounds

There is accumulating evidence that sulfated lipids, sulfated oligosaccharides and other sulfated compounds are reactive with selectins in a manner that interferes with selectin interactions with their natural ligands. In the report we describe the ability of sulfated lipids (sulfatides and gangliosides) and multimeric forms of sulfated sialic acid to block binding of P- and E-selectin-Ig to neutrophils. The in vivo ability of these compounds to block lung injury in rats following i.v. infusion of purified cobra venom factor (CVF), which induces injury that is L- and P-selectin dependent, was also determined as well as effects on recruitment of neutrophils, as measured by lung myeloperoxidase. There was a significant correlation between the ability of sulfated lipids and sialyl compounds to interfere in vitro with P-selectin-Ig binding to neutrophils and to protect against P-selectin-dependent acute lung injury induced by CVF. The biological effects of these sulfated compounds were also associated with diminished accumulation of neutrophils. The protective effects of these compounds may be linked to their ability to interfere with P- selectin binding to counter-receptors on neutrophils.