Epstein-Barr virus latent membrane protein-1 oncogene deletions: correlations with malignancy in Epstein-Barr virus--associated lymphoproliferative disorders and malignant lymphomas

LMP-1, an Epstein-Barr viral (EBV) latency protein, is considered a viral oncogene because of its ability to transform rodent fibroblasts in vivo and render them tumorigenic in nude mice. In human B cells, EBV LMP-1 induces DNA synthesis and abrogates apoptosis. LMP-1 is expressed in EBV-transformed lymphoblastoid cell lines, nasopharyngeal carcinoma (NPC), a subset of Hodgkin's disease (HD), and in EBV-associated lymphoproliferative disorders (EBV-LPDs). Recently, focused deletions near the 3' end of the LMP-1 gene (del-LMP-1, amino acids 346-355), in a region functionally related to the half-life to the LMP-1 protein, have been reported frequently in human immunodeficiency virus (HIV)- associated HD (100%) and EBV+ Malaysian and Danish peripheral T-cell lymphomas (100%, 61% respectively), but less frequently in cases of HD not associated with HIV (28%, 33%) and infectious mononucleosis (33%). To further investigate the potential relationship of del-LMP-1 to EBV- LPDs associated with immunosuppression or immunodeficiency, we studied 39 EBV-associated lymphoproliferations (10 benign, 29 malignant) from four distinct clinical settings: posttransplant (4 malignant, 1 reactive); HIV+ (18 malignant, 2 reactive); nonimmunodeficiency malignant lymphoma (ML) (7 cases); and sporadic EBV infection with lymphoid hyperplasia (7 cases). The presence of EBV within lymphoid cells was confirmed by EBV EBER1 RNA in situ hybridization or by polymerase chain reaction (PCR) analysis. EBV strain type and LMP-1 deletion status were determined by PCR. EBV strain types segregated into two distinct distributions: HIV+ (9 A; 11 B) and non-HIV (19 A, 0 B), consistent with previous reports. Overall, del-LMP-1 were found in 1 of 5 (20%) Burkitt lymphomas (BL); 17 of 24 (71%) aggressive non- Hodgkin's lymphoma (agg-NHL), and 2 of 10 (20%) reactive lymphoid proliferations. Of the agg-NHLs, del-LMP-1 were present in 4 of 4 PT-ML (100%); 10 of 15 HIV+ ML (67%); and 3 of 5 nonimmunodeficiency malignant lymphoma (ML, 60%). A total of 2 of 7 (28%) sporadic EBV- associated lymphoid hyperplasias contained a del-LMP-1. All del-LMP-1 were identical by DNA sequence analysis. No correlation was identified between the presence of del-LMP-1 and the EBV strain type observed. The high incidence of del-LMP-1 observed in agg-NHLs (71%), in contrast to the relatively low incidence observed in reactive lymphoid proliferations (28%), suggests that the deleted form may be preferentially selected in lymphomatous processes. All posttransplant agg-NHLs contained a del-LMP-1, and a similar frequency of del-LMP-1 was observed in both HIV-associated ML (66%) and nonimmunodeficiency ML (60%), suggesting that impairment of immune function alone is not a requirement for the expansion of malignant cells infected by EBV stains containing the deleted LMP-1 gene.     

Phase II trial of oral 4-demethoxydaunorubicin in patients with non-small cell lung cancer

4-Demethoxydaunorubicin (4-DMDR) is an orally active analog of daunorubicin that in preclinical testing has demonstrated greater antitumor activity and less cardiotoxicity than its parent compound. Thirty-two patients with metastatic non-small cell lung cancer received 4-DMDR at a dose of 40-50 mg/m2 orally every 21 days. Thirteen patients had received no prior chemotherapy. Among the 30 adequately treated patients, one major response lasting 5.2 months was observed. Leukopenia 10-14 days after treatment was the most commonly observed toxicity. With an overall observed major response rate of 3.3% in 30 patients, the predicted true response rate is less than or equal to 16% (p = 0.05). At the dose and schedule studied in this group of patients with non-small cell lung cancer, 4-DMDR had only marginal activity.     

Phase I Study of Elliptinium (2-N-Methyl-9-Hydroxyellipticinium)

Elliptinium (2-N-methyl-9-hydroxyellipticinium), a chemotherapeutic agent whose mechanism of action has not been completely elucidated, intercalates into DNA. In this Phase I clinical trial, the schedule of drug administration consisted of weekly intravenous infusions. Twenty-nine patients were evaluable for toxicity. The initial dose level was 40 mg/m² and was escalated to 150 mg/m² through six levels. The dose-limiting side effects were emesis, xerostomia, and azotemia. The lack of myelosuppression was the most striking feature. Objective responses (partial remission, minor response) were seen in one patient each with Hodgkin's disease, non-Hodgkin's lymphoma, breast cancer, and nasopharyngeal carcinoma. We recommend a Phase II evaluation of elliptinium at a dose of 100 mg/m² on a weekly schedule.     

Renal Arterial and Venous Endothelin in Hypertensive Patients with or Without Renal Artery Stenosis

Immunoreactive endothelin (ir-ET) levels were measured in the renal veins and aorta of 43 untreated hypertensive patients immediately before renal angiography. None of the patients used antihypertensive medication. Twenty-seven patients had renal artery stenosis, 17 of which were unilateral and 10 bilateral. Seven of the 17 patients with unilateral renal artery stenosis had an elevated renin ratio. Of the 16 patients with essential hypertension 6 had a unilateral small kidney with a normal blood supply. Although there was a trend towards higher levels of ir-ET in patients with renal artery stenosis, no significant differences in endothelin levels (venous or arterial) were found between different groups of patients or groups of kidneys. More than 75% of kidneys extracted endothelin, there being no significant differences between groups of kidneys. In conclusion, our data demonstrate that endothelin levels and renal endothelin extraction are comparable in essential hypertension and in hypertension associated with renal artery stenosis. Whereas renal uptake or endothelin is the rule, some kidneys, however, release this peptide irrespective of the presence or absence of renal artery stenosis.     

Xanthone additives for blood storage that maintain its potential for oxygen delivery. I. 2-Hydroxyethoxy- and 2-ethoxy-6-(5-tetrazoyl) xanthones in citrate-phosphate-dextrose-adenine (CPDA-1) blood

Two xanthones, 2-hydroxyethoxy-6-(5-tetrazoyl) (BW A440C) and 2-ethoxy- 6-(5-tetraozyl) (BW A827C), are members of a chemical series tested in vitro as potential additives to citrate-phosphate-dextrose-adenine (CPDA-1) medium for blood storage. P50 was maintained in the presence of these compounds during 42 days' storage by a partial maintenance of 2,3 diphosphoglycerate (2,3 DPG) and by a direct effect on hemoglobin previously reported for BW A827C. Red cell 2,3 DPG levels for BW A440C (n = 5), BW A827C (n = 5), and control (n = 6), respectively, were 3.38 +/− 0.47, 3.44 +/− 0.25, and 1.20 +/− 0.10 mM +/− SEM on day 7; 1.16 +/− 0.13, 1.52 +/− 0.37, and 0.16 +/− 0.02 mM on day 21; and 0.67 +/− 0.09, 0.61 +/− 0.08, and 0.06 +/− 0.006 mM on day 42. Red cell adenine triphosphate levels at the same time intervals were 1.84 +/− 0.09, 1.46 +/− 0.18, and 2.11 +/− 0.04 mM; 2.10 +/− 0.05, 2.07 +/− 0.17, and 2.13 +/− 0.05 mM; and 1.42 +/− 0.13, 1.37 +/− 0.13, and 1.38 +/− 0.06 mM, respectively. The degree of hemolysis was less with the addition of the compounds, and the methemoglobin formation, plasma Na+ and K+, and lactate production were unaffected by the compounds.     

Growth Hormone Treatment in Short Children with Chronic Renal Failure and after Renal Transplantation: Combined Data from European Clinical Trials

Growth retardation is common in children with chronic renal failure (CRF). To investigate the efficacy and safety of recombinant human growth hormone treatment in such children and in children after renal transplantation, 43 prepubertal children with CRF, and 30 prepubertal and 25 pubertal patients with a renal transplant were studied. Data are reported for 31, 26 and 17 of these patients, respectively. Median height velocity increased from 4.2 to 9.8 cm/year during the first year of treatment, and to 6.8 cm/year during the second year of treatment in the patients with CRF. In the prepubertal transplant group, median height velocity changed from 3.5 to 8.4 cm/year during the first year and to 5.4 cm/year during the second year. In the pubertal transplant group, median height velocity increased from 3.2 to 6.6 cm/year during the first year and was 4.5 cm/year during the second year. The gain in height SDS for the prepubertal children in both the CRF and transplant groups was approximately 1 SD over 2 years. Treatment was well tolerated, and renal function did not change significantly in any group.