AR Patients Research Articles

Risk-directed therapy for childhood acute lymphoblastic leukemia. Results of the associazione italiana ematologia oncologia pediatrica '82 studies

In 1982, the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) started its third-generation study, aiming to improve previous results obtained by AIEOP '79 study and to deliver a standardized treatment to most Italian children with acute lymphoblastic leukemia (ALL). We treated 902 children (older than 1 year and younger than 15 years of age) with newly diagnosed ALL in multicenter studies of risk-directed therapy (111 low risk [LR] from Study 8201; 570 average risk [AR] from Study 8202; and 117 and 104 high risk [HR] from Studies 8303 and 8503, respectively). Induction therapy was composed of vincristine, prednisone, and asparaginase for LR or AR patients and these agents plus daunorubicin, (Study 8503) or vincristine, prednisone, cytarabine, and intermediate-dose methotrexate (Study 8303) for HR patients. Central nervous system (CNS) preventive therapy consisted of intrathecal methotrexate only (LR), intrathecal methotrexate plus 18 Gy cranial irradiation (AR and HR Study 8503), or high-dose (HD) cytarabine (HR Study 8303). Reinduction therapy was vincristine/prednisone/daunorubicin for AR patients with cyclophosphamide added for HR patients in Study 8303 and HD asparaginase in Study 8503. LR patients did not receive intensification therapy. Continuation therapy comprised 6-mercaptopurine plus methotrexate and monthly pulses with vincristine plus prednisone for all patients, except for HR patients in Study 8303 who also received teniposide plus cytarabine. Weekly HD asparaginase was also given in Study 8503. Duration of treatment was 24 months for Studies 8201 and 8202, 15 months for Study 8303, and 22 months for Study 8503. The overall complete remission (CR) rate was 94.7% (97.3% for LR, 94.9% for AR, and 93.2% for HR). Overall 7-year event-free survival (EFS) was 53.6% (standard error [SE], 1.8). EFS was 60.8% in LR (SE, 4.7), 60.6% in AR at 7 years (SE, 4.7), and 18.5% in Study 8303 (HR) at 5 years (SE, 3.8). Because of the poor result in HR patients, a successor study (8503) was developed that yielded a 5-year EFS of 46.1% (SE, 5.1). Site-specific relapse rates were 18.5% (LR), 13.4% (AR), 35.1% (HR on 8303), and 18.3% (HR in Study 8503) for bone marrow and 9.2%, 7.9%, 17.5%, and 19.3%, respectively, for the CNS (isolated). Isolated testicular relapse was observed in 3.9% of male patients. This risk-directed therapy cured at least 50% of patients with ALL with relatively nonintensive therapy. The 80% overall survival rate for LR and AR patients at 7 years suggested that the total cure rate may be higher than 50% because of the significant salvage rate for patients who received antimetabolite-based therapy initially.

Oxidative metabolism of circulating granulocytes in adult respiratory distress syndrome

Among the different mechanisms involved, polymorphonuclear leukocytes (PMNs) may play a central role in the pathogenesis of adult respiratory distress syndrome (ARDS). PMNs were evaluated in 15 patients with ARDS, in 21 at risk of developing ARDS (AR), and in 36 controls (C). Spontaneous and opsonized zymosan (OZ), phorbol myristate acetate (PMA), and F-Met-Leu-Phe (F-M-L-P)-stimulated oxygen radical production was measured by luminol- and lucigenin-enhanced chemiluminescence (CL). Spontaneous CL activity of PMNs from ARDS patients was significantly greater than that from the PMN control (luminol CL, 2.8 ± 0.6 vs. 0.8 ± 0.1 mV, p <0.001; lucigenin CL, 2.0 ± 0.6 vs. 0.30 ± 0.04 mV, p <0.001), and the CL value from AR patients (luminol CL, 1.3 ± 0.2 mV, p <0.001 vs. C; Lucigenin CL, 0.8 ± 0.1 mV, p <0.001 vs. C) was found to be between the ARDS and C patients. The peak of PMA-stimulated CL occurred earlier and it was significantly higher in ARDS patients than in AR patients (p <0.05) and controls (p <0.001). When the CL response was elicited with F-M-L-P, no difference among the three groups was found. When stimulated with OZ, the peak CL generated by PMNs from ARDS patients was significantly depressed compared with controls (luminol CL, 26.7 ± 1.8 vs. 40.9 ± 2.3 mV, p <0.01; lucigenin CL, 5.0 ± 0.4 vs. 7.4 ± 0.5 mV, p <0.005) with a similar result being obtained from AR patients (luminol CL, 32.1 ± 2.5 mV, p <0.01 vs. C). Plasma from ARDS and AR patients showed a defective opsonizing capacity, suggesting in vivo complement consumption in both patient groups. No correlation between the severity of hypoxemia, the cause of ARDS, the outcome, and the different PMN functions could be established. Our results are in agreement with a determinant role of PMNs in the development of ARDS. The opposite metabolic responses may explain both the pulmonary injury and the increased susceptibility to infections observed in patients at risk of or with ARDS.

Follicular fluid-induced acrosome reaction distinguishes a subgroup of men with unexplained infertility not identified by semen analysis

We compared the ability of sperm to undergo follicular fluid-induced acrosome reaction in vitro in fertile men and patients with unexplained infertility. After capacitation under optimum conditions, 28% of sperm from fertile men undergo acrosome reaction after follicular fluid exposure, whereas only 7% of the cells react spontaneously. In 15 men with unexplained infertility, 6 patients showed lack of acrosome reaction, whereas 9 men had sperm acrosome reactions similar to that of fertile men. However, in this cohort under study, semen characteristics of AR(+) and AR(-) patients were similar. In addition to inducing sperm acrosome reaction, follicular fluid also promoted significant changes in motion characteristics of capacitated sperm. Sperm curvilinear velocity (Vc) increased significantly after exposure to follicular fluid though linearity remained unchanged. The largest difference in cumulative Vc occurred at 90 microns/s. Assessing the ability of capacitated sperm to acrosome react may have clinical significance in predicting whether such sperm are capable of fertilizing an ovum.

Antigen-induced eustachian tube obstruction: An intranasal provocative challenge test

ETO and symptoms of AR have been demonstrated to develop after an intranasal provocative antigen-challenge test. To determine the antigen dose required to produce ETO, intranasal insufflations of increasing amounts of pollen (ragweed or timothy) from 0.1 to 100 mg were delivered to 29 patients, ages 20 to 31 yr with AR who were skin test positive or had elevated serum-IgE antibodies to ragweed or timothy but not pine pollen. Our results demonstrated ETO developed in four ears at 0.05 mg of pollen, in one at 0.5 mg, in four at 1 mg, in 28 at 10 mg, in 15 at 50 mg, and in two at 100 mg of pollen. ETO persisted from 2 to 120 hr. Dose responses and duration of ETO were compared to patients' serum-IgE antibodies that ranged from 3% to 36% B T (median 26.4%). The patients with the highest serum-IgE antibody values (≥26.4%) required lower antigen-dose challenges (≤10 mg) to develop ETO ( p ≤ 0.01) that also persisted longer (≤48 hr) p ≤ 0.05. Symptoms of AR developed with an antigen dose that was less than the antigen dose that resulted in the development of ETO in 22 patients and at the same antigen dose in the other seven subjects. At a later date, these same subjects were also challenged intranasally with 50 mg of pine pollen after which no symptoms of AR or development of ETO were noted. In summary, the expression of ETO after provocative intranasal pollen challenge in AR patients is an immune-mediated reaction that is antigen-dose dependent and related to serum-IgE antibody titer.

Use of left ventricular filling and ejection patterns in assessing severity of chronic mitral and aortic regurgitation

To determine whether left ventricular (LV) filling and ejection patterns can be used to characterize the severity of mitral and aortic regurgitation (MR and AR), normalized volume vs time curves derived from left ventriculograms were plotted using a computer-based image analysis system. These patterns were measured in 20 normal subjects, 14 patients with MR and 21 patients with AR. In addition, timeaveraged volume changes (dV/dt) and diameter changes (dD/dt), stroke or filling volume, and ejection or filling fraction were measured during systole and diastole. The patients with volume overload were separated into 4 groups based on symptoms: asymptomatic (MR, 7 patients, AR, 10 patients); congestive heart failure (CHF) (MR, 7 patients, AR, 11 patients). Ejection fraction was significantly depressed in both CHF groups, even though stroke volume index was significantly increased in all groups. The temporal pattern of diastolic filling in patients with CHF secondary to MR and AR demonstrated slower, later diastolic filling compared with normal subjects, while in asymptomatic MR, diastolic filling was more rapid than in normal subjects. Diastolic filling patterns were similar to normal in asymptomatic AR patients. Temporal systolic emptying was slower in patients with CHF secondary to AR; emptying patterns in asymptomatic MR patients were similar to those of normal subjects; late systolic emptying was accelerated in patients with asymptomatic AR. Thus, there were filling and emptying abnormalities in all stages of volume overload secondary to regurgitation. These values can be measured noninvasively with scintigraphic angiography and echocardiography and may be useful as indicators of progressive ventricular dysfunction in patients with chronic valvular regurgitation.