The sensitivity of relapsed acute lymphoblastic leukemia (ALL) to treatment with steroids was assessed by measuring bone marrow blast, whole-cell glucocorticoid receptor (GR) levels and serial ...cytokinetic and clinical responses to steroids, both as single agents and in combination reinduction chemotherapy. GR levels ranged widely, from 1800 to 47,800 sites/cell (median 16,000), and did not differ significantly from levels measured in newly diagnosed patients (p = 0.50). Nineteen of the 48 children studied had GR levels measured both at diagnosis and relapse, and in 14 the values at relapse were either decreased or increased by more than 25%. For nine children, the sensitivity to a three-day oral course of dexamethasone alone (6 mg/m2 per day) was estimated from daily leukocyte counts and serial bone marrow cytokinetic studies. A clinical oncolytic effect of dexamethasone was associated with a reduction in the marrow cell proliferating compartment, as judged from labeling indices, mitotic indices and percent S + G2 + M in five patients. We found, however, that GR levels either alone or combined with clinical or cytokinetic responses to dexamethasone as a single agent did not reliably identify patients who were likely to respond favorably to reinduction with steroid-containing combination chemotherapy. The 35 children who successfully attained subsequent remissions had GR levels similar to those who failed (p = 0.35). While not statistically significant, two observations suggest an association between lower receptor content and drug resistance. Receptor levels from patients with ALL who relapsed while on chemotherapy were appreciably lower (median 15,700, n = 31) than GR levels from patients who relapsed off therapy (median 20,300, n = 17) (p = 0.08). Moreover, three of seven patients with serial studies, whose GR levels at relapse were lower than at diagnosis, failed reinduction--compared to only one of twelve whose levels were either increased or remained unchanged (p = 0.11). Although not having any obvious clinical utility, studies of GR at diagnosis and at relapse may aid in clarifying mechanisms of drug resistance in leukemic blasts.
The pathologic and clinical features of 31 cases of childhood non‐Hodgkin's lymphoma (NHL) were reviewed retrospectively using Rappaport's classification and a modification of the Ann Arbor staging ...system. Twenty‐nine (93.5%) of the patients had diffuse and 2 (6.5%) had nodular lymphoma. Diffuse histiocytic lymphoma accounted for 10 cases (32.3%), diffuse undifferentiated for 9 (29%), and diffuse lymphocytic, poorly differentiated for 5 (16.1%). Five cases (16.1%) were unclassifiable. No cases of well‐differentiated lymphocytic or mixed cell lymphoma were found. A modified classification was attempted, which included also large basophilic cell (LBC), convoluted T‐lymphocytic (CTL), and Burkitt's lymphomas. These pathologic subgroups accounted for 35.4%, 16.1%, and 6.5% of the cases, respectively. The patients were almost equally divided between clinically localized and generalized stages, and their survival was stage‐dependent. The overall survival was 32.3%; the 3‐year survival was 50% for Stages I and II, compared to 7.7% for Stages III and IV. The gastrointestinal tract was the most common site of origin. In 22% of the cases, the disease originated in extra‐lymphatic tissues. Central nervous system involvement occurred in 10 of 31 children (32%), and a leukemic picture developed in 6 of 31 (19%). The CTL lymphomas were confined to the mediastinum, whereas the LBC lymphomas arose mostly in Waldeyer's ring and Peyer's patches. We conclude that the extent of the disease as determined by clinical staging has prognostic significance in childhood NHL. The prognostic value of the histological classification could not be clearly established from our data.
Hormones and regional brain blood flow Goldman, H; Skelley, E B; Sandman, C A ...
Pharmacology, biochemistry and behavior,
1976, Volume:
5, Issue:
Suppl 1
Journal Article
Peer reviewed
Acute effects of the hormones, estradiol-17beta and alphaMSH, and of neonatal pretreatment with alphaMSH on the flow of blood to regions of the brains of conscious adult rats have been determined ...with an indicator distribution technique. As previously reported, flows were reduced in most areas within 10 min after intravenous administration of alphaMSH; only the occipital cortex was spared. Though these effects were transitroy for most areas, perfusion of pons and medulla, cerebellum, hippocampus and parietal cortex was still low by 20 min. However, pretreatment with alphaMSH during infancy led to persistent behavioral changes which were not accompanied by flow differences. Assuming that flow changes reflect functional changes, the rapid responses to alphaMSH suggest an explanation for the effects of this hormone on visual learning and on the determination of subsequent learning behavior. By contrast, estradiol, within 10 min after injection, increased flow to most regions of the brain, especially the frontal cortex, hippocampus, basal ganglia and cerebellum; females were more affected than males. Flow changes were greater than those elicited by more obvious behavior-modifying drugs. Compared to alphaMSH, the flow data for estradiol suggest a physiologic basis for a behavioral effect which is likely to be different yet, perhaps, equally profound.
High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute ...lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.
In a clinical trial involving asymptomatic, HIV-seropositive subjects treated with either the HIV-1 immunogen (an inactivated, gp120-depleted HIV-1 virus in incomplete Freund's adjuvant) or an ...adjuvant control, we examined the relationship between changes in the percentage of CD4 cells over time and early clinical markers of HIV disease progression. Subjects who had an early clinical event were more likely to have a greater decline in the percentage of CD4 cells than those subjects who did not have a clinical event (p = 0.054). The greatest decline in CD4 percentage occurred within 10 weeks prior to a clinical event (mean 11% decrease from baseline). Subjects from the quartile with the greatest decline in CD4 percentage had a fivefold greater risk of having a clinical event than subjects from the quartile with the second largest decline (p = 0.045). These results demonstrate a relationship between changes in the percentage of CD4 cells and early clinical events. Further validation of this association may be useful in clinical monitoring and in evaluating therapies to treat HIV infection.
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