Combination 6-mercaptopurine-adriamycin in refractory adult acute leukemia.

Remission induction therapy with 6MP and adriamycin in combination was administered to 19 adult leukemic patients refractory to previous therapy. Eight patients also received vincristine and prednisone. Thirteen patients had acute myelogenous leukemia, 3 undifferentiated leukemia, and 3 blastic transformation of chronic myelogenous leukemia. Four patients achieved remission but in only 2 were the remissions complete. Eleven patients failed to respond. Ten of the 19 patients developed unexpected severe liver toxicity manifested by a clinical picture of cholestasis (in the majority) or ascending cholangitis (in 2 patients). In the postmortem examination of 8 patients there was cholestasis and mild to severe hepatocellular damage in all.

RP 64477: a potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase with low systemic bioavailability.

RP 64477 (N-butyl-3-(p-decyloxybenzamido)-4-(methylthio)benzamide) has been shown to be a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (EC 2.3.1.26; ACAT) in intestinal, hepatic, adrenal, and arterial tissue preparations obtained from a range of animal species. Drug concentrations producing 50% inhibition of enzyme activity (IC50 values) ranged from 14-283 nM. Inhibition by RP 64477 in a rabbit intestinal enzyme preparation was shown to be non-competitive with respect to the substrate oleoyl-CoA. In whole cell assays using human intestinal (CaCo-2), hepatic HepG2) and monocytic (THP-1) cell lines, RP 64477 inhibited ACAT activity with IC50s of 113, 503, and 180 nM, respectively. RP 64477 (0.03% w/w by diet) reduced significantly cholesterol absorption in cholesterol/cholic acid-fed rats from 94+/- 8% to 65 +/- 4%. In cholesterol-fed rabbits, cholesterol absorption was reduced from 72 +/- 5% to 50 +/-5% and 44 +/- 5% at dose levels of 10 and 30 mg kg-1 b.i.d., respectively. Plasma cholesterol levels were reduced dose-dependently in both cholesterol/cholic-acid-fed rats and cholesterol-fed rabbits. Neither cholesterol absorption nor plasma cholesterol levels were reduced significantly in animals maintained on standard laboratory diets. Pharmacokinetic studies indicated that RP 64477 were very poorly absorbed following oral administration to rats. Plasma levels of drug were < 2 ng mL-1 following a dose of 2000 mg kg-1 p.o.. When radiolabelled RP 64477 was administered orally, limited absorption was indicated by the overwhelming elimination of radioactivity in the faces (96.4% of administered material) coupled with low renal clearance (0.6% of dose) and biliary excretion (0.05% of dose). In conclusion, this work shows that RP 64477 is a potent inhibitor of ACAT obtained from a range of animal species and man. Inhibition of cholesterol absorption and hypocholesterolaemic activity has been demonstrated in rats and rabbits maintained on diets supplemented with cholesterol. Pharmacokinetic studies indicate low systemic exposure to RP 64477 as a result of limited absorption of this drug.

Castleman's disease of the leptomeninges. Report of three cases.

Castleman's disease is a rare, benign lymphoproliferative disorder that usually arises in lymph nodes, most commonly in the mediastinum. The authors report the clinical and pathological features of three patients with localized Castleman's disease of the leptomeninges. There were two women, aged 63 and 82 years, and one 25-year-old man. Two patients had progressive focal motor seizures of 3 and 24 months' duration, and the third patient presented acutely with generalized seizures. The clinical diagnosis was meningioma in each case, based on computerized tomography scans, cerebral arteriography, and the operative findings. All three lesions arose in the leptomeninges, compressed the underlying cerebral cortex, and infiltrated the overlying dura to a variable extent. Surgical excision of the tumor resulted in marked clinical improvement in all three patients. Histologically, two cases were classified as the hyaline-vascular type and one as the plasma cell type. Immunohistochemical stains of the latter case revealed a monoclonal population of mature plasma cells. Only a few scattered polyclonal plasma cells were seen in the other two cases. The authors conclude that Castleman's disease involving the leptomeninges is a rare disorder that may mimic meningioma clinically and radiographically.

Analysis of progesterone in unextracted serum: a method using danazol [17 alpha-pregn-4-en-20-yno(2, 3-d) isoxazol-17-ol] a blocker of steroid binding to proteins.

A technique has been developed in which progesterone may be measured by radioimmunoassay in unextracted serum. The method depends on the displacement of progesterone from serum binding proteins by danazol, [17 alpha-pregn-4-en-20-yno (2,3-d) isoxazol-17-ol], a compound which also blocks recombination of free progesterone with proteins and does not cross react with the progesterone antiserum. This new method saves time and labour, and fulfills the criteria of sensitivity and precision for clinical use. The results correlate well with those of conventional assays for progesterone.

Lateral pontine and extrapontine myelinolysis associated with hypernatremia and hyperglycemia.

Efforts to understand and prevent pontine and extrapontine myelinolysis have focused on the correction of hyponatremia, but controversy persists. We report a woman who presented in hyperosmolar diabetic coma with hypernatremia (169 mEq/l) and hyperglycemia (954 mg/dl). Plasma sodium rapidly increased to 188 mEq/l before gradually returning to normal. She remained obtunded and died 21 days later. Autopsy showed widespread, symmetrical demyelination involving the subcortical white matter, corpus callosum, anterior commissure, extreme, external, and internal capsules, fornix, thalamus, cerebellum, and lateral pons. The central pons and lateral geniculate nuclei were uninvolved. This case illustrates that lateral pontine and extrapontine myelinolysis can be associated with hypernatremia and hyperosmolality. In both hypo- and hypernatremic states, the significant event may be an increase in serum sodium or serum osmolality of sufficient rapidity and magnitude.

Fine-needle aspiration cytology of prostate: experience in a nonacademic practice.

Fine-needle aspiration cytology of the prostate is becoming increasingly accepted and used in the United States. This is a report of the experience of a nonacademic practice in which the aspirations were performed by a number of urologists, usually in the office, and were interpreted by a number of pathologists with varying degrees of experience in cytopathology. Of 187 patients, 159 had smears adequate for evaluation, and 99 had histologic/substantiating clinical follow-up for comparison. The resulting specificity was 97%, sensitivity was 91%, and the false-negative rate was 9%. These figures compare favorably with those reported in studies from academic university-based practices.

The problem of hirsutism in women.

Women commonly complain of excess facial or body hair. There are generally no other abnormal physical findings and the relevance of other symptoms, especially those related to the menstrual cycle, may be unclear. The theme of androgen excess provides an explanation for the sign and various symptoms, and suggests certain pathology. Rational therapy can be based on and understanding of the hormonal processes involved in the development of secondary sexual hair. Treatment of simple hirsutism is well tolerated even in prolonged courses, and in most cases produces a satisfactory cosmetric result.

Hirsutism: pathogenesis and treatment.

When hirsutism is recognised as an endocrinopathy, a rational approach to treatment can be devised. In simple hirsutism, the ovaries are the most likely source of excess androgen production, and demonstrate a wide range of pathology. The adrenal cortex is sometimes of prime importance but is more frequently a contributor of androgen precursors. Long term hormonal suppressive treatment will successfully control hirsutism in the majority. Antiandrogens constitute a potential treatment for future years; physical methods of depilation remain as useful adjuncts to medical therapy.

Chronic treatment regimens for hirsutism in women: effect on blood production rates of testosterone and on hair growth.

Twenty-five women with hirsutism were studied before and during treatment aimed empirically at suppresing testosterone production by adrenals, ovaries or both. Mean basal plasma testosterone was 70 plus or minus 30 ng/dl, significantly (P less than 0.01) higher than the mean of twenty-three normal women; basal metabolic clearance rate (MCR) of testosterone was also higher (P less than 0.01) than that reported for normal women. Production rate (PR) of testosterone exceeded 417 mug/24 h (1 SD above the mean reported for normal women), in nineteen of the twenty-five patients. After 4 months, small dose betamethasone therapy (0.5 mg at bed time) had reduced the mean PR of testosterone in thirteen patients from 509 mug/24 h to 356 mug/24 h (P = 0.05); anovulatory steroids reduced mean PR of testosterone in nine from 612 mug/24 h to 345 mug/24 h (P less than 0.05, greater than 0.025), and the combination of both therapies in ten reduced PR of testosterone from 528 mug/24 h to 148 mug/24 h (P less than 0.001). The latter regimen had moderate success in reducing hair growth (in six out of ten). Fourteen of the twenty-five claimed benefit in hirsutism and all thirteen with acne were improved. In individual cases, clinical benefit did not correlate well with reduction in PR of testosterone. Freedom from undesirable side effects allows these well-accepted forms of treatment to be given even longer trials.

Two dicentric Y isochromosomes, one without and the Yqh heterochromatic segment: review of the Y isochromosomes.

Two women with primary amenorrhoea and few other stigmata of Turner's syndrome were found to be chromosome mosaics: 45,X/46,X,idic(Y). In Case 1, the dicentric isochromosome Y was found to have a long-arm breakpoint of formation. This structure was interpreted as containing two Y short arms and centromeres separated by a region derived from the proximal Y long arm. One of the centromeres in the Case 1--idic(Y) was suppressed in 80% of cells in blood, and in these cells it appeared as a regular Y-shaped chromosome. In Case 2 the idic(Y) was derived by a short-arm breakpoint of formation. In all the dicentrics of this case with one primary constriction (functional monocentrics) there was a single Cd band. In the 10% of dicentrics with two primary constrictions, there were two Cd bands. It is argued that the instability of sex isochromosomes is due to this functional dicentricity in some cells. These cases are compared with 42 other Y isochromosomes with various short- and long-arm breakpoints of formation. It is suggested that some of the nonheterochromatic, nonfluorescent Y chromosomes previously reported may be explained as dicentric i(Y) with proximal long-arm breakpoints of formation and one suppressed centromere.

Klinefelter's syndrome: experiences with 24 patients.

Twenty-four karotypically proven patients with Klinefelter's syndrome were studied. The majority suffered from disorders of personality and social adjustment. All were poorly educated. Two-thirds showed gynaecomastia and all had small testes. Eunuchoid body proportions were seen in the majority of patients. Half the patients had plasma androgen levels in the low normal range; in the rest the levels were subnormal. The serum LH level was elevated in 80% and could not be adequately suppressed by exogenous androgens in seven out of nine patients. Abnormalities of carbohydrate metabolism were demonstrated in seven patients. Bilateral mastectomy was a valuable form of therapy, but androgens were withheld for phychosocial reasons.

Cyclic presentation of central macular oedema.

We present the case of a young lady with unilateral pars planitis and associated cystoid macular oedema in whom visual symptoms fluctuated regularly during successive menstrual cycles. To date no such presentation of central macular oedema has been reported in the literature.

Spontaneous pneumomediastinum and diabetic ketoacidosis.

Spontaneous pneumomediastinum is a rare complication of diabetic ketoacidosis. We report two patients with this complication who presented to a Sydney hospital within one week. Although both patients were young backpackers, staying at the same hostel, we believe this was coincidental.

Arteriographic demonstration of intravenous tumor extension.

The arteriographic demonstration of a linear, striated arterial pattern in the anatomic course of the draining vein is reliable evidence of venous extension by a tumor and represents the supply to the intravenous component of the neoplasm. In addition to its previously described occurrence with hypernephromas, this report documents the characteristic angiographic appearance with hepatocellular tumors and a retroperitoneal osteosarcoma as reliable evidence of tumor extension into the inferior vena cava. It is possible that in some cases, the parallel arteries represent markedly enlarged vasa vasorum of the involved venous structure. The frequent invasion of the inferior vena cava by hepatomas and the importance of inferior vena cavography in their angiographic evaluation is also emphasized.

Routine use of low-dose intravenous insulin infusion in severe hyperglycaemia.

A review if presented of the use of low-dose insulin infusion in the management of 58 episodes of severe diabetic hyperglycaemia. Neutral insulin in a dosage of 2-4 units per hour is infused via a paediatric giving set to achieve a sustained physiological elevation of insulin levels. This method is safe, simple and rapidly effective in lowering the blood glucose level, the mean rate of fall (62 mg/100 ml/hr, or 11% per hour) being unaffected by prior insulin therapy, acidosis or ketonuria. Classification of the hyperglycaemia as ketoacidotic or hyperosmolar is unnecessary before insulin therapy is instituted, as the relative decline in glucose level is the same in the hyperosmolar non-ketotic group as in the others. Proven infection significantly lowers the rate of fall of glucose level. Hypoglycaemia and hypokalaemia are rare during low-dose infusion. Early and adequate replacement with potassium phosphate is recommended, oral potassium supplements being continued for several days. Bicarbonate therapy is rarely indicated in the management of acidosis. No patient had cerebral oedema during treatment, and one elderly patient with extensive pneumonia and empyema died during the infusion. It is suggested that continuation of low-dose insulin infusion, together with 5% dextrose solution, after the plasma glucose level reaches 200 mg/100 ml, may hasten the clearance of ketones, preventing relapse.