Regression of experimental Burkitt's lymphoma induced by Epstein-Barr virus-immortalized human B cells

Epstein-Barr virus (EBV)-immortalized human B cells survive only transiently when injected subcutaneously into athymic mice, whereas Burkitt's lymphoma cells give rise to progressively growing subcutaneous tumors. In this study, we tested whether these Burkitt's tumors could be induced to regress via a bystander effect induced by EBV-immortalized B cells. Simultaneous inoculation of EBV-immortalized B cells and Burkitt's lymphoma cells in the same subcutaneous site resulted in tumors that regressed with necrosis and scarring. Similarly, simultaneous inoculation of EBV-immortalized B cells and Burkitt's lymphoma cells in separate subcutaneous sites resulted in regression of a proportion of the Burkitt's tumors. Furthermore, most of the established human Burkitt's tumors regressed with necrosis and scarring after intratumor inoculations with EBV-immortalized B cells. The EBV-immortalized B cells continued to exert this antitumor effect even when killed with irradiation. The experimental approach to Burkitt's lymphoma treatment described here exploits the ability of athymic mice to reject EBV-immortalized B cells to target an effective antitumor response to malignant cells normally incapable of eliciting it.     

Some properties of marrow derived adherent cells in tissue culture

It has previously been shown that monolayer cultures derived adherent cells (MDAC), apparently consisting of fibroblasts, macrophages, epithelioid cells, and fat cells, can support long-term stem cell proliferation in vitro. In the present study, the hematopoietic support capability of murine MDAC monolayers was confirmed and the cultured cells further characterized with respect to the following properties: esterase I activity, complement (C3) receptors, IgG (Fc) receptors, colony stimulating activity (csa) production, and collagen synthesis. The cultures were also examined immunohistochemically to localize fibronectin, laminin, and collagen synthesis and to identify the collagen subtypes synthesized. MDAC morphology was as described in previous studies, although fat cells were few in number. It was found that MDAC included some cells with esterase I activity and C3 receptors. Fc receptors were not, however, detected, nor did the cultures produce csa, indicating that mononuclear phagocytes were not present. MDAC synthesized collagen types I and III and also fibronectin. Staining for epithelial basement membrane proteins (collagen types IV and V and laminin) was negative. The results indicate that the vast majority of these cultured MDAC were fibroblasts.     

Studies on levamisole--induced agranulocytosis

Widespread clinical trials of leavo-tetramisole (levamisole) as an immunopotentiating agent in rheumatoid arthritis, metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis (AGC) in 2.5%-13% of patients. Other than a relationship with prolonged high dosage, very little is known regarding the pathogenesis of levamisole-induced AGC. Whereas leukoagglutination was negative, fluorochromatic microgranulocytotoxicity (GCY) tests were positive with serum from 10 of 10 acutely neutropenic patients. The antibody was IgM, reacted with 100% of unrelated granulocytes, but not with T or B lymphocytes. Some sera also reacted with monocytes and the myeloid cell line, K-562. Tests for antigen-antibody complexes or cold autoantibodies were negative. Although clinical evidence strongly suggests a haptene (drug) mechanism, in vitro mixing experiments were also negative. An alternative choice parallels the model of aldomet- induced Coombs'-positive hemolytic anemia. Finally, GCY first became positive 2-3 mo prior to the onset of AGC on two patients, suggesting the possibility of identifying those at risk well before the onset of neutropenia.     

Effects of intestinal stasis on intercellular adhesion molecule 1 expression in the rat: Role of enteric bacteria

BACKGROUND & AIMS: The mechanisms underlying the inflammatory changes associated with intestinal stasis are poorly understood. The objective of this study was to assess whether endothelial expression of intercellular adhesion molecule 1 (ICAM-1) and leukocyte recruitment are altered after intestinal stasis. METHODS: ICAM-1 expression and granulocyte recruitment were quantified in different tissues of Sprague- Dawley rats using the double-radiolabeled monoclonal antibody technique and peroxidase activity, respectively. RESULTS: Both constitutive and endotoxin-induced ICAM-1 expression were significantly higher in the cecum than in distal colon, a finding that cannot be explained by a difference in endothelial surface area between the two organs. Surgical procedures to improve cecal stool flow (cecostomy, ileocecostomy) elicited a significant decrease in constitutive ICAM-1 expression in both cecum and distal colon. Tissue peroxidase activity was normally higher in cecum than in distal colon, and this difference was significantly reduced by ileocecostomy. Oral administration of antibiotics (kanamycin and/or metronidazole for 2 days) significantly reduced constitutive ICAM-1 expression in the cecum, but not in the distal colon. CONCLUSIONS: This study indicates that intestinal stasis is associated with an increased expression of ICAM-1 and granulocyte infiltration, which may be mediated by enteric bacteria. (Gastroenterology 1997 Jun;112(6):1971-8)     

Prognostic significance of arrhythmia in tetralogy of fallot after intracardiac repair

The significance of arrhythmia and conduction defects was studied in 395 patients who underwent intracardiac repair of tetralogy of Fallot between 1958 and 1976. In 91 of these patients (group I), the median date of repair was 1964 and all underwent stress testing. In 107 patients (group II), the median date of repair was significantly later (1971), but all subjects were too young for stress testing. The remaining 197 patients (group III, median date of repair 1963) included all those who did not participate in stress testing or who had died; 42 of these patients were later excluded from analysis because of insufficient electrocardiographic records. The overall incidence of any form of arrhythmia (19 percent) was the same for each group. However, in group II (patients who underwent intracardiac repair more recently), no tachyarrhythmia was observed and there were fewer patients with 1° atrioventricular (A-V) block (p <0.001) and more patients with complete right bundle branch block (p <0.001) than in groups I and III. In two patients (both in group I), unexpected, late sudden death unrelated to strenuous physical activity occurred. Arrhythmia was least common in patients with primary intracardiac repair and more common in those with either palliation before intracardiac repair or multiple intracardiac repairs. In group I, 41 of 91 patients with arrhythmia of even minor degree at rest (n = 13) or exercise (n = 28) had a significantly larger heart, greater right ventricular pressure and lesser exercise performance than did those without arrhythmia, thus suggesting the presence of residual abnormality or dysfunction. No tachyarrhythmia was induced by exercise in this study. Patients with either arrhythmia or bifascicular block have generally had a benign course without strong evidence of progression of arrhythmia.     

Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia

No constant genetic alteration has yet been unravelled in T-cell acute lymphoblastic leukemia (T-ALL), and, to date, the most frequent alteration, the SIL-TAL1 deletion, is found in approximately 20% of cases. Recently, two genes have been identified, the multiple tumor- suppressor gene 1 (MTS1) and multiple tumor-suppressor gene 2 (MTS2), whose products inhibit cell cycle progression. A characterization of the MTS locus organization allowed to determine the incidence of MTS1 and MTS2 inactivation in T-ALL. MTS1 and MTS2 configurations were determined by Southern blotting using 8 probes in 59 patients with T- ALL (40 children and 19 adults). Biallelic MTS1 inactivation by deletions and/or rearrangements was observed in 45 cases (76%). Monoallelic alterations were found in 6 cases (10%). The second MTS1 allele was studied in the 4 cases with available material. A point mutation was found in 2 cases. The lack of MTS1 mRNA expression was observed by Northern blot analysis in a third case. A normal single- strand conformation polymorphism pattern of MTS1 exons 1alpha and 2 was found and MTS1 RNA was detected in the fourth case, but a rearrangement occurring 5' to MTS1 exon 1 alpha deleting MTS1 exon 1Beta was documented. One case presented a complex rearrangement. Germline configuration for MTS1 and MTS2 was found in only 7 cases. The localization of the 17 breakpoints occurring in the MTS locus were determined. Ten of them (59%) are clustered in a 6-kb region located 5 kb downstream to the newly identified MTS1 exon 1Beta. No rearrangement disrupting MTS2 was detected and more rearrangements spared MTS2 than MTS1 (P<.01). MTS1 but not MTS2 RNA was detected by Northern blotting in the human thymus. These data strongly suggest that MTS1 is the functional target of rearrangements in T-ALL. MTS1 inactivation, observed in at least 80% of T-ALL, is the most consistent genetic defect found in this disease to date.     

Histopathology of the thymus of patients with acute lymphoblastic leukemia and lymphoblastic lymphoma in complete clinical remission

The histologic features of thymuses from three patients who underwent thymectomy for acute lymphoblastic leukemia or lymphoblastic lymphoma in complete clinical remission are described. The thymuses from all three patients were fibrotic with a variability in the appearance of the lobules. Some of the lobules consisted predominantly of epithelial cells with small numbers of mature appearing lymphocytes, while other lobules were expanded and composed predominantly of cells having morphological features of immature lymphoid cells consistent with residual or recurrent disease.     

The effect of chemotherapy on the kinetics and proliferative capacity of normal and tumorous tissues in vivo

The proliferative state of a given tissue is a major determinant of its sensitivity to both phase-specific and cycle-specific chemotherapeutic agents. To study the extent of injury induced by antitumor agents to normal and tumorous tissues, a technique for following DNA synthesis as reflected in the incorporation of tritiated thymidine (3H-TdR) into DNA was compared to the conventional radioautographic technique of the labeling index (LI) and to the functional kinetic technique of granulocyte colony formation in vitro. Alterations in DNA synthesis induced by a single dose of cyclophosphamide in normal and tumorous tissues in vivo paralleled in many respects the changes seen when the more time-consuming techniques of the LI or granulocyte colony formation were employed. However, the recovery of granulocyte colony formation after cyclophosphamide therapy lagged behind the recovery of DNA synthesis in the bone marrow, obscuring a kinetic event of potential therapeutic significance. The determination of DNA synthesis simultaneously in normal and tumorous tissues in vivo was easy to perform and supplied therapeutically pertinent results comparatively quickly.