Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease.

PURPOSE: We assessed the cumulative risk of malignancies following treatment for Hodgkin's disease in childhood and adolescence and investigated related patient and treatment characteristics. PATIENTS AND METHODS: Medical records of 499 Hodgkin's disease patients treated between 1962 and 1993 were reviewed. There were 385 adolescents (> or = 10 years of age at diagnosis) and 114 preadolescents (< 10 years). Most patients (n = 346) were treated with radiation plus multiagent chemotherapy, while 30 received only chemotherapy and 123 only radiation therapy. Radiation doses ranged from 20 to 42 Gy. RESULTS: At a median follow-up duration of 9 years (range, 0.1 to 27.4), 25 patients have had second malignancies: 19 solid tumors, four acute nonlymphoblastic leukemias (ANLLs), 1 non-Hodgkin's lymphoma (NHL), and one chronic myeloid leukemia (CML). Three patients have had a third malignancy. The estimated cumulative risk of second malignancies increased from 1.5% at 5 years to 7.7% at 15 years. All but two of the patients with second malignancies were > or = 10 years of age at initial diagnosis, which reflects the higher risk among patients treated for Hodgkin's disease as adolescents (P = .01). Second malignancies were more common among female patients (P = .0002), even when those breast cancer were excluded (P = .007), and in those treated for recurrent Hodgkin's disease (P = .02). Patients with ANLL/NHL were older at diagnosis of Hodgkin's disease than those with solid tumors, (median age, 18.3 v 13.8 years; P = .04). There was no difference between groups treated with radiation therapy alone, chemotherapy alone, or radiation plus multiagent chemotherapy. CONCLUSION: Adolescents treated for Hodgkin's disease are at greater at risk of second malignancies than younger patients. Overall, adolescent females treated for recurrent Hodgkin's disease appear to be at greatest risk, while preadolescents appear to be protected from this late complication.

Arterial blood pressure control during hindlimb and forelimb contraction in the dog.

This study examined the differential reflex cardiovascular responses evoked by separate contractions of the right hindlimb and forelimb and established the mechanism of a regional reflex vasodilation associated with hindlimb skeletal muscle contraction. The two groups of skeletal muscle were contracted separately by electrical stimulation (2-48 Hz) of the peripheral motor nerves. The left nonexercising hindlimb was perfused at constant flow. All blood pressure-regulating mechanisms were intact. Arterial blood pressure (ABP), left nonexercising hindlimb perfusion pressure (HLPP), and heart rate (HR) were recorded. HR was increased by skeletal muscle contraction. This response was independent of muscle group and contraction frequency. Increases in both ABP and HLPP were produced by high-frequency contractions (greater than 16 Hz) of either the hindlimb or forelimb. Decreases were evoked only by hindlimb contractions (greater than 8 Hz). The nonexercising skeletal muscle vascular bed contributed to this systemic depressor response by vasodilating. The mechanism involved a contraction-induced withdrawal of sympathetic nerve activity to that vascular bed. Concomitant with this response was an increase in heart rate that was blocked with propranolol. Similar heart rate changes evoked by forelimb contractions also were blocked with propranolol. These data indicate that sympathetic outflow to resting skeletal muscle depends on the origin and magnitude of the afferent signal from the contracting skeletal muscle.

Carotid sinus and blood pressure control during hindlimb and forelimb contractions.

Arterial blood pressure (ABP) regulation during exercise involves in part medullary interaction of afferent information from contracting skeletal muscles and the major baroreceptors. This study examined in chloralose-anesthetized dogs the role of the carotid sinus baroreceptors in modulating reflex changes in ABP, nonexercising hindlimb skeletal muscle vascular resistance, and heart rate (HR) evoked by two separately contracting (4, 16, and 48 Hz) groups of skeletal muscle, the right hindlimb and forelimb. When arterial and cardiopulmonary baroreceptor afferent information was interrupted, hindlimb contractions evoked a greater augmentation of ABP (16 and 48 Hz) and no further increase in nonexercising hindlimb perfusion pressure (HLPP). Forelimb contractions, which in the presence of baroreceptors had not affected ABP (4 and 16 Hz), now reduced it profoundly. Nonexercising HLPP, which increased independently of contraction frequency, now was decreased by 4 Hz, not affected by 16 Hz, and increased by 48 Hz. The increase in HR was abolished. Increasing carotid sinus pressure to 220 mmHg in vagotomized dogs abolished the reflex changes evoked by hindlimb skeletal muscle contractions. However, forelimb contractions continued to decrease ABP. Nonexercising HLPP and HR did not change from the precontraction values. These data indicate that the carotid sinus baroreceptor could buffer completely those changes in the selected cardiovascular variables evoked by hindlimb but not forelimb skeletal muscle contractions. Thus the role of the carotid sinus baroreceptors in controlling ABP during exercise depends on the group of skeletal muscle initiating the somatic afferent signal and its influence on the contraction-induced distribution of the efferent signals.

Contribution of prostaglandins to muscle blood flow in anesthetized dogs at rest, during exercise, and following inflow occlusion.

The role of locally formed cyclo-oxygenase products (endoperoxide intermediates, prostaglandins, or prostacyclins) in resistance to blood flow was studied in the hindlimbs of anesthetized dogs during rest, during exercise, and following release of inflow occlusion. Meclofenamic acid, indomethacin, or sodium meclofenamate reduced mean resting blood flows of 86, 113, and 118 ml/min to 54, 82, and 67 ml/min, respectively. Inhibitors of prostaglandin synthesis reduced the vasodilator response to arachidonic acid by 81%. In addition, prostaglandin synthesis inhibitors attenuated the hyperemic responses following inflow occlusions in the resting hindlimb. The attenuation was most marked following a 1-second occlusion (74%) and progressively less following a 10-second (44%) and a 300-second (24%) occlusion. However, the portion of the total postocclusive hyperemic response attributable to prostaglandins was constant and independent of occlusion duration. Inhibition of prostaglandin synthesis did not affect the hyperemia of exercise, but reduced significantly the postocclusion hyperemia that followed the release of a 1-second (63%) and a 2-second (43%) period of inflow occlusion in the exercising hindlimb; attenuation was minor following a 10-second occlusion (10%). In three of four exercising hindlimbs, the portion of the postocclusion hyperemia attributable to prostaglandins was inversely related to the duration of the occlusion. These data indicate that locally synthesized cyclo-oxygenase products, possibly prostaglandins, are important in the maintenance of blood flow in resting but not exercising muscle, contribute significantly to postocclusive hyperemia in resting and exercising hindlimbs, and mediate the hyperemia that follows occlusions of 5 seconds or less in resting and 2 seconds or less in exercising hindlimbs.

Action of angiotensin II on renal blood flow and function during hemorrhagic shock.

The purpose of this study was to evaluate during hemorrhagic hypotension and shock the effect of angiotensin II on renal blood flow, glomerular filtration rate, and sodium and potassium excretions, and to determine its role in the development of irreversible hemorrhagic shock. Anesthetized dogs were subjected to a hemorrhagic shock protocol. Angiotensin II was infused at 100 ng/kg/min i.v. from 50 mm Hg initial hemorrhage until the experiment was terminated. The survival time from 50 mm Hg initial hemorrhage to reinfusion was increased significantly from 2.7 +/- 0.5 h to 4.7 +/- 0.8 h by exogenous angiotensin II. However, once shock had developed, the survival time from reinfusion to 50 mm Hg normovolemic hemorrhagic shock was not affected by exogenous angiotensin II (4.4 +/- 1.4 to 3.6 +/- 0.7 h.) During hemorrhagic shock, exogenous angiotensin II significantly increased sodium excretion and total renal blood flow. Glomerular filtration rate, potassium excretion, and arterial sodium and potassium concentrations were not affected. These data indicate that angiotensin II prolonged the development of irreversible hemorrhagic shock and selectively increased sodium excretion and total renal blood flow.

Action of lithium on the adrenergic nerve ending.

The effect of lithium on adrenergic neurotransmission was investigated using the lateral saphenous vein of the dog as a model of the neuroeffector process. Helically cut vein strips were mounted in either an organ bath where tension was recorded or in a superfusion system where both tension and the overflow of [3H]norepinephrine and its metabolites were determined. Lithium was used at both therapeutic (0.5-1.5 mEq/l) and toxic (2.5-14.4 mEq/l) concentrations. Lithium had no effect on basal tension or overflow [3H]norepinephrine. At therapeutic concentrations, the neuronal amine uptake mechanism was augmented, whereas at toxic concentrations monoamine oxidase was inhibited. In therapeutic concentrations, lithium attenuated the response of the adrenergic nerve ending to electrical stimulation (0.5-10 Hz). This response was due in part to the augmentation of the neuronal amine uptake mechanism. At toxic concentrations, responses to low frequency (0.2-1.0 Hz) electrical stimulation were augmented, whereas those at higher frequencies (5-10 Hz) were attenuated. Inhibition of monoamine oxidase by lithium accounted for only a part of the augmented overflow of transmitter and subsequent contractile response since inhibition of monoamine oxidase did not prevent the augmentation by lithium of [3H]norepinephrine overflow. The mechanism by which lithium in both therapeutic and toxic concentrations reduces transmitter overflow and subsequently contractile responses remains to be elucidated. Thus, lithium alters the disposition and release of norepinephrine and, as a result, affects adrenergic neurotransmission.

Increased reactivity of venous smooth muscle by small decreases in extracellular sodium.

In dog saphenous vein strips, decreases in extracellular sodium from 5% to 23% did not alter basal tension, but progressively increased tension developed during electrical stimulation (1.0 to 10 Hz). The augmentation did not occur with similar reductions in chloride ions. When osmolality was maintained with sucrose, the response to electrical stimulation also was enhanced with a 5% reduction in sodium ions, but did not increase further with larger sodium reductions. The enhancement was due to some effect on the smooth muscle cells, because the overflow of [7-3H]norepinephrine during electrical stimulation was unaffected by the sodium reduction, whereas contractions caused by norepinephrine and barium chloride were potentiated. The potentiation did not depend on increased influx of extracellular calcium, because contractions induced by acetylcholine were unaffected by sodium reduction; and after blocking calcium influx with verapamil, the norepinephrine contractions still were augmented. It was concluded that a decrease in extracellular sodium by 5% (from the normal value of 143.3--131.1 meq/1) can enhance the response of venous smooth muscle to adrenergic stimuli.

Fatal fat embolism in a patient with sickle-beta+ thalassemia.

We describe a case of an adolescent with sickle-beta+ thalassemia who developed fatal fat embolism syndrome. After presenting with bone pain, the patient developed mental status changes, hypoxemia, and died following cardiorespiratory arrest.

Renin response and angiotensinogen control during graded hemorrhage and shock in the dog.

Hemorrhage and hemorrhagic hypotension have been shown to be potent stimulators of renin release. However, the relationship between angiotensinogen consumption and angiotensinogen production has yet to be completely defined during this type of circulatory stress. Peripheral renin activity increased progressively as the blood pressure was decreased stepwise by hemorrhage to 50 mmHg and remained elevated throughout the shock phase of the experiment. Angiotensinogen did not change from control (809 ng/ml) throughout hemorrhabic hypotension and shock. During hemorrhagic hypotension, with the infusion of the angiotensin antagonist, [1-sarcosine, 8-alanine]angiotensin II, angiotensinogen concentration fell progressively from 693 to 208 ng/ml at 50 mmHg. Intravenous angiotensin II infused continuously after the mean blood pressure reached 50 mmHg significantly elevated plasma angiotensinogen concentration. In conclusion, during hemorrhagic hypotension and shock, the kidney and the liver appeared capable of maintaining elevated plasma renin activity and adequate plasma renin substrate, angiotensinogen, respectively. The mechanism responsible for the maintenance of plasma angiotensinogen is suggested to involve a positive-feedback effect of angiotensin II on the liver.