Therapeutic failure of uterine fibroid embolization caused by underlying leiomyosarcoma.

The authors describe an unusual case in which continued growth of uterine fibroids in a postmenopausal patient after polyvinyl alcohol embolization therapy prompted hysterectomy, which revealed an underlying leiomyosarcoma. The surgery was nearly fatal as a result of venous bleeding, and parasitization of blood from adjacent bowel by the tumor was noted. The difficulty of preoperative diagnosis of leiomyosarcoma and the need for diligent follow-up after uterine fibroid embolization are discussed.

Pathological examination and the reporting of lung cancer specimens.

The Lung Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative first met in January of 1994. Included in the membership were three pathologists who, with the other members of the DSG, felt that a useful contribution to the work of the group would be a recommendation on standardized examination and reporting of lung cancer specimens. This review summarizes the consensus of the Lung Cancer DSG pathologists based on their review of the literature and proposes a standard synoptic report, the Primary Lung Cancer Check-Off Sheet. If generally adopted, this standard would improve the quality of reporting of clinical and pathological stage information. Such high-quality staging information is essential to define patient populations for clinical trials and for outcome analyses.

Cardioprotective action of sodium gamma-hydroxybutyrate against isoproterenol induced myocardial damage.

In this study, the effects of graded doses of isoproterenol (IP) on the heart were examined in untreated gerbils and in gerbils anaesthetized with gamma-hydroxybutyrate (GHB), an endogenous metabolite with energy sparing properties. We were interested in the cardioprotective potential of GHB. IP was administered intraperitoneally in doses of 0.1, 0.3. 2.5 and 10.0 mg/kg to different groups of gerbils. Half the gerbils in each treatment group received 500 mg/kg of GHB 30 min before IP, and 250 mg/kg at three subsequent 2-hour intervals. The remaining gerbils in each treatment group received saline at these time points. The animals were sacrificed after 8 hours. The accumulation of neutral fat droplets in the sarcoplasm was the most consistent effect of IP. The highest dose also produced some scattered myofibre death. The accumulation of fat in the cells could be estimated semi-quantitatively using a histochemical reaction for succinic dehydrogenase, and the volume of fat could be measured more accurately by electron microscopic morphometry. These measurements showed that IP produced a three to five-fold increase in sarcoplasmic fat volume. GHB either abolished or significantly reduced the accumulation of fat and it also completely prevented the myofibre death caused by the highest doses of IP. This cardioprotective effect of GHB was independent of its hypothermic action. Based on this experience, ultrastructural morphometry of sarcoplasmic fat appears to be a promising method for evaluating cardioprotective measures.

The protective effect of magnesium on acute catecholamine cardiotoxicity in the neonate.

Neonates undergoing heart surgery are exposed to high levels of circulating catecholamines. Our objective was to determine to what extent administration of magnesium counters epinephrine-induced cardiotoxicity. We assessed left ventricular function (pressure-volume data obtained by the conductance catheter/micromanometer technique) and ultrastructure in newborn pigs 3 to 5 days of age before and after administration of epinephrine alone (2 micrograms/kg/min, group A, n = 6) and simultaneously with magnesium sulfate (8 mmol/L, 5 ml/hr, group B, n = 6). Plasma levels of magnesium were maintained at 200% to 250% of control, and ionized calcium was maintained at normal levels. During administration of epinephrine, there was a significant increase in end-systolic elastance from 8.9 +/- 2 to 15 +/- 3 mm Hg/ml in group A and from 7.8 +/- 2 to 16 +/- 3 mm Hg/ml in group B (p < 0.05). This increase was accompanied by an increase in chamber stiffness index (p < 0.05) and shortening of the time constant of isovolumic relaxation (p < 0.05; group A, 19 +/- 3 to 13 +/- 3 msec; Group B, 20 +/- 2 to 15 +/- 2 msec). After epinephrine was discontinued, however, systolic and diastolic indexes returned to baseline levels in group B, whereas group A exhibited a significant reduction in end-systolic elastance (5 +/- 1 mm Hg/ml; p < 0.05) and an increase in chamber stiffness index (0.7 +/- 0.08 versus 0.4 +/- 0.1 ml-1; p < 0.05) and time constant (25 +/- 1 versus 19 +/- 3 msec). Left ventricular dysfunction in group A was associated with focal sarcolemmal rupture and mitochondrial swelling, whereas only minor reversible changes (microvesicular lipid accumulation) were seen in group B. We conclude that magnesium has a protective effect against epinephrine-induced cardiotoxicity because of its blocking action on calcium influx of ionized calcium and could be of therapeutic benefit in the perioperative period.

Effects of high plasma epinephrine and Ca2+ concentrations on neonatal myocardial function after ischemia.

Administration of catecholamines to newborn infants may potentiate reperfusion injury because of increased transsarcolemmal Ca2+ influx and the presence of less developed sarcoplasmic reticulum in the immature hearts. We investigated the effect of administration of epinephrine (1.5 micrograms/kg per minute for 120 minutes) before ischemia and modified serum ionized Ca2+ concentrations in the cardioplegic solution and perfusate on postischemic left ventricular systolic and diastolic function in 25 piglets (5 to 7 days old) undergoing 90 minutes of cold blood cardioplegic arrest. The piglets were divided into four groups; Ca2+ 1.2 mmol/L, group A (n = 6), Ca2+ 0.25 mmol/L, group B (n = 6), Ca2+ 1.2 mmol/L and epinephrine, group C (n = 6), Ca2+ 0.25 mmol/L and epinephrine, group D (n = 7). Left ventricular function was assessed by a conductance catheter in the left ventricle measuring end-systolic and end-diastolic pressure-volume relationships during transient vena caval occlusion. By analysis of covariance, only Ca2+ concentration was important in predicting ventricular function recovery after ischemia (p < 0.01). End-systolic elastance decreased in all groups after ischemia; the magnitude was significantly greater in the normal groups (51% versus 35%, p < 0.01). There was a significant increase in the chamber stiffness index after administration of epinephrine before ischemia (p < 0.05). Groups with low Ca2+ perfusate (B and D) had no change in chamber stiffness index after ischemia. In contrast, there was a significant increase in chamber stiffness in the normal Ca2+ groups with (C) or without (A) epinephrine after ischemia (p < 0.05). Adenosine triphosphate stores declined significantly in the normal Ca2+ groups--48% versus 18% in the low Ca2+ groups (p < 0.01). We conclude that low Ca2+ concentrations in the perfusate and cardioplegic solutions better preserve left ventricular function in the normal and in epinephrine-stressed neonatal heart after ischemia.

Age-related response to epinephrine-induced myocardial stress. A functional and ultrastructural study.

Left ventricular systolic and diastolic function before, during, and after a 2-hour intravenous infusion of epinephrine at either 0.5 micrograms/kg/min or 2 micrograms/kg/min were assessed by pressure-volume data obtained by conductance catheter micromanometer technique and correlated with cardiac ultrastructure and plasma levels of epinephrine in neonatal (3-5 days old, n = 12) versus adult (3-4 months old, n = 11) pigs. Administration of epinephrine at 0.5 micrograms/kg/min resulted in an increase in end-systolic elastance (Ees) only in adults, whereas at 2.0 micrograms/kg/min Ees increased in both groups. After 2-hour administration of epinephrine at 2.0 micrograms/kg/min, Ees decreased significantly (p less than 0.05) from the preinfusion baseline value of 8.9 +/- 2 (mean +/- SD) to 5 +/- 1.7 mm Hg/ml, and a significant (p less than 0.05) increase in left ventricular volume elasticity (VdP/dV) from 0.4 +/- 0.02 to 1.4 +/- 0.2 mm Hg occurred in neonates versus no change from baseline in either Ees or VdP/dV in the adults. These changes in the neonates were associated with sarcolemmal rupture and mitochondrial Ca2+ granule deposition versus normal cardiac ultrastructure in the adults. We conclude that the neonatal myocardium is more susceptible to cardiotoxicity from circulating epinephrine.

Cardioprotective effects of sodium gamma-hydroxybutyrate (GHB) on brain induced myocardial injury.

Gamma-hydroxybutyrate (GHB) was evaluated as a protective agent in a gerbil model of non-lethal myocardial injury that follows brain ischaemia. The accumulation of fat droplets in myocardial fibers following brain infarction was measured by electron microscopic morphometry and expressed as a percentage of the area of the sarcoplasm. GHB treatment significantly reduced the area occupied by lipid droplets compared with that found in saline treated controls measured both 10 hours (p less than .005) and 24 hours (p less than 0.05) after unilateral carotid ligation. GHB did not affect the ischaemic swelling of the brain.

Palisading granulomas associated with lung cancer.

A granulomatous response to neoplastic structures was found in three cases of resected small-cell anaplastic carcinoma of the lung. This consisted of almost continuous rims of palisading epithelioid cells surrounding viable, necrotizing, and necrotic tumor nests. None of the patients had received chemotherapy or radiation treatment prior to surgery, and no clinical, microbiological, or histological evidence of tuberculosis, fungal infection, or rheumatoid disease was found. The granulomatous rim seems to be a response to spontaneous tumor decay.

Quantitative evaluation of myocardial injury induced by acute cerebral ischaemia and its prevention by beta 1-adrenergic blockade. An ultrastructural morphometry study.

The protective effects of beta 1-adrenergic blockade with metoprolol (Betaloc Astra) were demonstrated in the gerbil model of myocardial injury provoked by acute ischaemic brain lesions. The myocardial injury was reversible and lipid droplet accumulation was its most striking morphological feature. These droplets were easy to measure in EM photographs and their size was expressed as percentage of sarcoplasmic volume. The EM data of fat accumulation were compared in hearts of carotid-ligated animals with and without metoprolol pretreatment, and in animals with the carotid isolated only, at standard intervals 3-48 h after operation. While in carotid-ligated-only animals the average myocardial fat contents rose to a peak of 1.9% at 10 h, in metoprolol pretreated animals the amount of fat was always significantly lower and started to return earlier to basal values (peak at 6 h, 1.1%). In carotid-isolated-only animals, fat accumulation peaked at 6-10 h (1.1%) and returned quickly to normal levels (0.34 +/- 0.18%). This effective pharmacological blockade with metoprolol strongly supports the concept of catecholamine mediation between acute intracranial lesions and myocardial injury. The background and significance of myocardial fat accumulation is discussed. The EM morphometry of fat droplets appears to be a suitable tool for quantification of reversible myocardial damage most useful for experimental evaluation of cardioprotective measures. As changes in succinic dehydrogenase histochemistry (from 'myofibrillar' to 'granular' pattern) correlated with EM measured fat accumulation, the simplicity and speed of the SDH method recommends itself for fast orientation about presence of myocardial damage.

Arterial resistance to neoplastic invasion.

The relevance of proteinase inhibitors to the resistance of arterial walls against neoplastic invasion was investigated in human and porcine vessels using plasminogen activators as model. No significant differences in the inhibitory potential of extracts from the vascular walls were found between pulmonary and systemic arteries. It is concluded that the proteinase - inhibitor system studied is not responsible for the immunity of arterial walls against neoplastic invasion. The lack of antineoplastic resistance of pulmonary arteries may be explained by lesser intraarterial blood pressure and hence a lower pressure gradient across the vessel wall in pulmonary as opposed to systemic arteries.

Antimetastatic effect of amiloride in an animal tumour model.

The diuretic Amiloride competitively inhibits the catalytic activity of the urokinase-type plasminogen activator on plasminogen in vitro. This effect was tested on a rat adenocarcinoma model and its invasive potential in the host lung. While the inhibitory effect on intact cell cultures of the tumour was slight, continuous exposure of tumour-injected animals to the drug completely prevented the formation of lung metastasis.

Reversible myocardial damage in gerbil brain ischaemia and its prevention by beta-adrenergic blockade.

Acute cerebral infarction in gerbils, produced by unilateral carotid ligation, was used as a model to investigate secondary myocardial changes. The extent of the myocardial damage revealed by succinic dehydrogenase (SDH) histochemistry and by release of myocardial creatine phosphokinase (MB-CK) was measured in gerbils sacrificed from 3 to 48 h after either carotid ligation, carotid isolation only or skin incision only. For technical reasons dead animals were excluded from analysis. Of surviving ligated animals 74% developed neurological deficits related to brain ischaemia. A significant weight increase in the ipsilateral hemisphere was found at 6-10 h, and maximal histological damage at 16 h, both partially reversible thereafter. Non-ligated animals did not develop neurological changes, and showed neither brain swelling nor cerebral histopathology. Extensive cardiac damage was shown by the SDH method from 3 h postoperatively, and confirmed by the elevated serum levels of MB-CK in the carotid-ligated group. The SDH changes were identical with those described in the hearts of patients with acute intracranial lesions, and appeared to be reversible. The effect of beta-adrenergic blockade was assessed in this model. Metoprolol tartrate injected intraperitoneally 3 h before and 1 h after carotid ligation (10 mg/kg each dose) significantly decreased the extent of myocardial damage as estimated both with SDH histochemistry and MB-CK serum levels. It had no effect on the ischaemic brain changes. These results strongly support the concept of catecholamine mediation of myocardial injury resulting from acute brain lesions.

Role of arterial occlusion in pulmonary scar cancers.

The pathogenesis of scars in lung carcinomas was studied in 57 consecutively resected small (less than or equal to 3 cm) peripheral lung cancers. Central, pigmented scars rich in elastic fibers were most frequently found in adenocarcinomas with predominantly non-destructive, intraalveolar growth pattern. In these cancers with elastin-rich scars, active neoplastic occlusion of one or more arteries was almost always found (96%). Infarction of tumor tissue and its supporting pulmonary stroma was frequently seen separating the central scar from the viable peripheral tumor zone. The elastic fibers of alveolar walls survived and condensed into a compact central scar. Based on these observations, it is suggested that scarring in peripheral lung cancers is often caused by mechanisms unique to the lung. Lung cancers often invade and occlude branches of pulmonary arteries, causing ischaemic necrosis (infarction) of the neoplasm and its stroma. In these neoplasms, often growing mainly in air spaces and preserving the pulmonary framework as their stroma, the elastic fibers of the aLveoli remain preserved despite necrosis, so that the alveolar elastic collapses to form the characteristic elastin-rich scar following absorption of necrotic debris.

The effect of nonviral liver damage on the T-lymphocyte helper/suppressor ratio.

In the present investigation an attempt was made to ascertain whether nonviral liver impairment in rats affects the THelper/TSuppressor ratio. Two hepatotoxic agents were used: (i) galactosamine (GA), which causes a drug-induced hepatitis-like damage, and (ii) orotic acid (OA), which induces fatty changes. Since these two substances act as antidotes to one another they were administered to rats either separately or simultaneously. GA caused severe liver damage documented by a 104-, 48-, and 1.6- fold rise in the plasma concentrations of ALT, AST, and ALP and by multiple foci of hepatocyte necrosis. This was followed by a drop in TH/TS ratio from 2.25 observed in the controls to 0.89 in the GA-treated rats. All of these phenomena were prevented by concurrent administration of GA and OA. OA alone did not show an effect on the liver with respect to changes in plasma enzyme concentrations and by light microscopic analysis. However, OA caused a drop in the TH/TS ratio from 2.25 to 1.55. Neither GA nor OA produced a change in TH/TS ratios in in vitro experiments.