A phase I study of interleukin-6 after autologous bone marrow transplantation for patients with poor prognosis Hodgkin's disease.

We performed a pilot study of human recombinant IL-6 (SDZ ILs 969) in 6 patients with poor prognosis Hodgkin's disease following autologous bone marrow transplantation (ABMT) to determine its safety and tolerability. IL-6 was administered the day following bone marrow infusion by subcutaneous injection once daily at a dose of 1 micro/kg/day to 3 patients and 2.5 microg/kg/day to 3 patients and was continued for 6 weeks or until platelet engraftment (>50 x 10(9)/L independent of transfusion). No severe or life threatening toxicities were seen at either dose level. A reversible elevation in alkaline phosphatase occurred in 4 patients and all patients complained of headache, myalgias, and fever. Gastrointestinal toxicity was low, grade 3-4 mucositis occured less frequently than in similarly-treated historical controls receiving GM-CSF. Serum concentrations of other cytokines such as IL-3 and G-CSF after ABMT differed from results obtained in transplant recipients given GM-CSF. The median time to an ANC >0.5 x 10(9)/L was 25.5 days and to a platelet count of >20 x 10(9)/L independat of transfusion was 35.5 days. Engraftment was no different from controls. Five patients relapsed at a median of 5 months post-ABMT and four remain alive at a median of 12 months post-ABMT. We conclude that IL-6 administration is safe and well tolerated in patients following ABMT. Further efforts to evaluate its effect on hematopietic recovery as well as relapse following transplantation in a larger patient series are warranted.

Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease before intensive therapy and autologous bone marrow transplantation.

PURPOSE: To evaluate the efficacy of carmustine (BCNU), etoposide, cytarabine (Ara-C), and melphalan (mini-BEAM) as salvage therapy in patients with relapsed or refractory Hodgkin's disease who were potentially eligible to undergo intensive therapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Forty-four patients with refractory or relapsed Hodgkin's disease after front-line combination chemotherapy referred for consideration of ABMT were treated with mini-BEAM (BCNU 60 mg/m2 on day 1, etoposide 75 mg/m2 on days 2 to 5, Ara-C 100 mg/m2 twice per day on days 2 to 5, and melphalan 30 mg/m2 on day 6) to maximum response. Eleven patients were refractory to primary chemotherapy. Twenty-three patients were treated in first relapse and 10 in second or subsequent relapse; 21 received mini-BEAM as their first salvage regimen. Patients were restaged to determine disease status immediately before intensive therapy and transplant. RESULTS: The overall response rate was 84% (exact 95% confidence interval [CI], 70% to 92%), with a complete response (CR) rate of 32% (95% CI, 20% to 47%) and a partial response (PR) rate of 52%. No treatment-related deaths were observed. Myelosuppression was the major toxicity. Almost all patients required platelet transfusions. Eighty-four percent were given RBC transfusions, and 54% required intravenous antibiotics for fever while neutropenic. CONCLUSION: Mini-BEAM is a safe and effective regimen for treatment of refractory or relapsed Hodgkin's disease. Further studies are required to determine if responding patients have improved disease-free survival (DFS) after intensive therapy and ABMT.

Atypical thyroglossal duct cyst: a rare cause for a solitary cold thyroid nodule in childhood.

A case of an atypical thyroglossal duct cyst is described in a 9-year-old boy who presented with a lateral neck mass that was hypofunctioning on thyroid scan and clinically indistinguishable from a thyroid nodule. Preoperative fine needle aspiration biopsy results demonstrating abundant, normal appearing squamous epithelial cells and keratinaceous material was suggestive of the diagnosis. Definitive diagnosis was made only after complete mobilization of the left lobe of the thyroid gland and cyst resection. A standard Sistrunk procedure was performed, and cyst excision was accomplished without resection of the left lobe of the thyroid gland. Microscopic examination disclosed a keratinizing pseudostratified squamous epithelium that has not been previously reported with thyroglossal duct cysts.

Cell cycle analysis of p53-induced cell death in murine erythroleukemia cells.

A temperature-sensitive mutant of murine p53 (p53Val-135) was transfected by electroporation into murine erythroleukemia cells (DP16-1) lacking endogenous expression of p53. While the transfected cells grew normally in the presence of mutant p53 (37.5 degrees C), wild-type p53 (32.5 degrees C) was associated with a rapid loss of cell viability. Genomic DNA extracted at 32.5 degrees C was seen to be fragmented into a characteristic ladder consistent with cell death due to apoptosis. Following synchronization by density arrest, transfected cells released into G1 at 32.5 degrees C were found to lose viability more rapidly than did randomly growing cultures. Following release into G1, cells became irreversibly committed to cell death after 4 h at 32.5 degrees C. Commitment to cell death correlated with the first appearance of fragmented DNA. Synchronized cells allowed to pass out of G1 prior to being placed at 32.5 degrees C continued to cycle until subsequently arrested in G1; loss of viability occurred following G1 arrest. In contrast to cells in G1, cells cultured at 32.5 degrees C for prolonged periods during S phase and G2/M, and then returned to 37.5 degrees C, did not become committed to cell death. G1 arrest at 37.5 degrees C, utilizing either mimosine or isoleucine deprivation, does not lead to rapid cell death. Upon transfer to 32.5 degrees C, these G1 synchronized cell populations quickly lost viability. Cells that were kept density arrested at 32.5 degrees C (G0) lost viability at a much slower rate than did cells released into G1. Taken together, these results indicate that wild-type p53 induces cell death in murine erythroleukemia cells and that this effect occurs predominantly in the G1 phase of actively cycling cells.

c-myb effects on kinetic events during MEL cell differentiation.

During dimethylsulfoxide (DMSO)-induced differentiation of Friend mouse erythroleukemia (MEL) cells there is a biphasic fall in c-myb mRNA levels. We have previously shown that constitutive expression of c-myb blocks differentiation. To delineate more accurately the point at which Myb blocks differentiation, MEL cells were transfected with a human c-myb construct under the control of the beta-globin promoter and enhancers. In concert with endogenous DMSO-induced globin transcription during MEL cell differentiation, the beta-globin c-myb transcription unit of the transfected plasmid is activated after 3-5 days of culture in media containing DMSO. Here we describe c-myb-transformed MEL clones which undergo delayed expression of the exogenous c-myb following 3-5 days of culture in DMSO. In contrast to wild-type MEL cells, both clones failed to display phenotypic markers of differentiation and continued to proliferate for up to 10 days of culture. These data suggest that the late fall in c-myb levels may be required in order for differentiation to occur. Additionally, we suggest that constitutive expression of c-myb does not block early commitment events such as activation of histone Hl', subsequent chromatin condensation, and alteration of proliferation-related gene expression. Taken together, these results show that c-myb acts very late in the process of differentiation.

Urea synthesis, nitrogen balance, and glucose turnover in growth-hormone-deficient children before and after growth hormone administration.

We measured the effect of human growth hormone (hGH) on urea synthesis, nitrogen retention, and glucose turnover in ten euthyroid growth hormone (GH)-deficient children before and after seven daily injections of 0.1 U/kg hGH. The patients were fed a weight-maintaining diet with 9% of energy derived from protein. Following an overnight fast, urea synthesis and glucose turnover were determined using a primed constant infusion of [15N2] urea and a constant infusion of [6,6-2H2] glucose. Human growth hormone produced a decrease in urea nitrogen synthesis from 6.8 +/- 0.5 to 4.2 +/- 0.4 mg/kg.h; (P less than .01), while plasma urea nitrogen decreased from 13.1 +/- 0.8 to 7.4 +/- 0.8 mg/dL; (P less than .01). The decrease in urea synthesis was reflected in a corresponding decrease in urine urea nitrogen excretion (-2.8 mg/kg.h). There was a significant correlation between plasma urea nitrogen and urea synthesis rate both before (r = 0.85, P less than .01) and after (r = 0.79, P less than .01) hGH treatment. In response to hGH, there was a rise in both plasma glucose (81.4 +/- 2.2 v 89.8 +/- 2.3 mg/dL; P less than .05) and insulin (5.7 +/- 0.8 v 13.1 +/- 3.0 microU/mL; P less than .05), however, glucose turnover remained unchanged (4.7 +/- 0.3 v 4.6 +/- 0.6 mg/kg.min). After seven days of growth hormone treatment, the patients were placed on 0.1 U/kg of hGH three times a week for 6 months, and their growth rate was calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid simultaneous assay of serum estrone, estradiol, and estriol in pregnant women using methyl ether acetate derivatives by capillary gas chromatography and electron-impact mass spectrometry.

A simple gas chromatographic--mass spectrometric method capable of measuring estrone, estradiol, and estriol simultaneously with a sensitivity close to that of radioimmunoassay has been developed. The estrogens in serum were extracted with diethyl ether, and internal standards (3-O-C2H3-estrone, 3-O-C2H3-estradiol, and 3-O-C2H3-estriol) were added, followed by converting to methyl ether compounds with an extractive alkylation procedure. The methyl ethers were then acetylated. Analyses were performed using a SP-2250 capillary column gas chromatograph coupled with an electron-impact mass spectrometer. The estrogen methyl ether acetate derivatives were more stable chemically and gave less fragmentation upon electron impact than the conventional trimethylsilyl derivatives. The use of selected ion monitoring of molecular ions and that of the corresponding internal standards (M + 3) provides a sensitivity down to 10 pg for estrone and estradiol and to 200 pg for estriol. The time required for the preparation of multiple samples is within 4 hours.

Micropenis. III. Primary hypogonadism, partial androgen insensitivity syndrome, and idiopathic disorders.

This paper, the third in a series, presents data from 28 patients with micropenis categorized as primary hypogonadism (11 subjects), partial androgen insensitivity (1 subject), idiopathic (6 subjects), and etiology undetermined (10 subjects). Among the 11 patients with primary hypogonadism, 8 presented with various degrees of gonadal dysgenesis, 1 was a true hermaphrodite and 2 had the Robinow syndrome. Nine of the 28 patients were raised as females: 5 with primary hypogonadism and 4 with undetermined etiology. Eleven of the 19 patients raised as males received androgen stimulation during prepubertal years and responded with penile growth. However, this growth response was temporary and did not appear to be predictive of eventual adult size of the penis. Generally, the prestimulation size of this group of patients is more predictive of adult penile size. Only 7 of the patients raised as males have attained adult somatic growth. Three out of the three with primary hypogonadism, the subject with partial androgen insensitivity, and one of three with idiopathic micropenis have below-normal adult penile length. These limited data suggest that growth potential of the micropenis may be greater among the patients with an idiopathic state than among those with primary hypogonadism and partial androgen insensitivity.

Micropenis. II. Hypogonadotropic hypogonadism.

This paper documents the case histories of 14 patients with hypogonadotropic hypogonadism and micropenis (penile length below 2.5 SD from the mean for the patient's chronlogical age, or for age corresponding to stage of sexual development). Nine of the patients were raised as males. Five of them received androgen for the purpose of stimulating penile growth: two realized normal adult penile length (-0.2 and -2.1 SD from normal mean length) whereas the other three had penile lengths significantly below the mean (-3.6, -4.6 and -5.2 SD from normal mean length). These data suggest that among hypogonadotropic patients with micropenis, those with prepubertal penile lengths between 2.5 and 3 SD below the mean may develop an adult penis of a length within the normal range. However, for those presenting with a shorter phallus, the expectation is that penile length will remain greater than 2 SD below the mean.

Micropenis. I. Criteria, etiologies and classification.

A micropenis is an abnormally small penis with a normal configuration. This finding constitues a sign not a diagnosis. The etiologies may be classified as hypogonadotropic hypogonadism, primary hypogonadism, androgen insensitivity, or idiopathic; among 45 patients, the respective percentages in these categories were 31, 24, 2 and 7% with 36% as yet undiagnosed. Various clinical syndromes may include a micropenis and can be classified in one of the etiologic categories. This paper provides the criteria for determining the presence of a micropenis. A phallic length which is 2.5 or more standard deviations below the mean should be considered as abnormal; for an infant of 0 to 5 months of age, the lower limit is 1.9 cm. The technique of penile measurement, determination of etiology, guidelines for sex of rearing and psychologic, surgical and medical management are discussed.

Treatment of Cushing's disease with bilateral adrenalectomy and autotransplantation.

2 Cases of childhood Cushing's disease have been treated with bilateral adrenalectomy and autotransplantation of adrenal tissue. Transplantation was unsuccessful in 1 case. In the other patient, replacement therapy was discontinued without any symptoms of hypo- or hyperadrenocorticism. Her urinary 17-hydroxycorticosteroids, free cortisol and aldosterone remain in the low normal range indicating functional adrenal tissue, probably a result of the transplant.

Studies of androgen production and binding in 13 male pseudohermaphrodites and 13 males with micropenis.

We studied androgen production by morphologic and biochemical criteria plus androgen binding by skin fibroblasts in 13 male pseudohermaphrodites and 13 males with micropenis, none of whom had evidence of androgen insensitivity. Seventeen of the 26 patients had evidence of deficient androgen production, suggesting this as the cause of their incomplete virilization in utero. Fibroblasts from all 26 patients demonstrated normal androgen binding and affinity of the steroid for the receptor. Although these results exclude a deficiency of androgen binding in these individuals, other end organ defects are possible. Guidelines for diagnosis and management of such patients are presented.

Diencephalic syndrome revisited.

This report details the histories of five patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. A review of an additional 67 patients indicates that the observations are not unique. The anatomic variability combined with the fact that the course of those who are treated is infinitely better than those left untreated adds urgency to the establishment of precise anatomic diagnosis. These considerations led to a critical review of the histories of the 72 patients. From this it can be stated that anteriorly and posteriorly placed tumors do exhibit subtle but significant differences in their clinical course, and roentgenograms of the optic foramina and analysis of the CSF cell and protein content appear warranted early in the investigation of emaciation from unknown cause. Further, an evaluation is made of the role of various radiologic techniques and of endocrine studies in establishing the diagnosis. Similarly, the relative merits of radiotherapy and/or surgery in the treatment of the disease are defined. Finally, the adequacy of the term diencephalic syndrome is discussed.

Treatment of cryptorchidism. Long-term prospective study.

We have presented preliminary findings on a long-term prospective study designed to (1) assess timing of orchiopexy, (2) eliminate unnecessary abdominal exploratory surgery, and (3) determine efficacy of orchiopexy on subsequent fertility and on malignant degeneration. Some suggestions for the management of this common congenital defect can be provided, but long-term results are lacking. A significant drop-out rate from this prospective study is expected with time; therefore, large patient numbers are needed to draw any valid conclusions at the time of postpubertal reassessment.