Evaluation of FDG PET in patients with cervical cancer.

UNLABELLED: Although many human cancers can be imaged by 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and PET, there is little clinical experience with FDG PET in cervical cancer. The purpose of this study was to evaluate the feasibility of FDG PET scans on patients with cervical cancer. METHODS: FDG PET scans were performed on 21 patients with histologically proven uterine cervical cancer (17 newly diagnosed, 4 recurrence). After two levels of transmission scanning, approximately 370 MBq FDG were injected, and dynamic scans over 60 min were obtained at the level of suspected tumors, followed by static scans. Postvoid scans were also obtained in 11 patients to minimize FDG activity in the urinary bladder. FDG uptake was interpreted visually and classified into 4 grades (0 = normal, 1 = probably normal, 2 = probably abnormal and 3 = definitely abnormal). For a semiquantitative index of FDG uptake in tumors, the standardized uptake value (SUV) corrected by predicted lean body mass (SUL) was calculated and compared. The detectability of lymph node metastases by PET was compared with that by CT. RESULTS: Of the 21 newly diagnosed or recurrent cancers, 16 (76%) were detected by FDG PET without use of postvoid imaging (i.e., interpreted as grade 2 or 3). The SULs of tumors ranged from 2.74-13.03, with a mean of 8.15 +/- 3.00 (SUV range 3.68-14.94, mean 10.31 +/- 3.19). There was no significant relationship between the SUL of cervical cancer and the clinical stage. Postvoid FDG PET images substantially reduced the tracer activity in the urinary bladder and improved the visualization of cervical cancers, with three additional cases detected using the postvoid images. In the 11 patients with postvoid imaging, all 11 cancers (100%) were detected. FDG PET detected lymph node metastases in 6 (86%) of 7 patients with known metastases, whereas CT was positive in 4 patients (57%), equivocal in 2 patients (29%) and negative in 1 patient (14%). All PET and CT scans were true-negative in the patients with no lymph node metastases (interpreted as grade 0 or 1 by PET, and as negative by CT). CONCLUSION: These preliminary data demonstrate the feasibility of FDG PET imaging in patients with cervical cancer. FDG PET appears to be promising for detecting untreated or recurrent cervical cancers and lymph node metastases, although the excreted FDG in the urine remains problematic in some cases.

Untreated primary lung and breast cancers: correlation between F-18 FDG kinetic rate constants and findings of in vitro studies.

PURPOSE: To compare kinetic modeling of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (F-18 FDG) between untreated primary lung and untreated primary breast cancers by using positron emission tomographic (PET) findings and to correlate these findings with findings of in vitro studies. MATERIALS AND METHODS: Nineteen patients (12 men, seven women; age range, 49-82 years) with untreated primary lung cancer and 17 women with untreated primary breast cancer (age range, 26-65 years) underwent 1-hour dynamic F-18 FDG PET. A three-compartment model was applied to F-18 FDG kinetics in tumors. The standard uptake value normalized for lean body mass (SUVlean) in tumors was measured 50-60 minutes after tracer injection. In vitro, thin-layer chromatography was performed to evaluate the intracellular phosphorylation of tritiated F-18 FDG in human lung cancer and breast cancer cell lines. RESULTS: At PET, lung cancer had a significantly (P < .003) higher rate constant for F-18 FDG phosphorylation (k3) and SUVlean than did breast cancer (0.164 +/- 0.150 [standard deviation] vs 0.043 +/- 0.018 and 8.25 +/- 3.28 vs 3.17 +/- 1.08, respectively). Breast cancer showed a significant correlation between k3 and SUVlean (r = .607, P < .01), although no such correlation was observed in lung cancer. In vitro studies showed phosphorylation of F-18 FDG in breast cancer cells was less complete in hyperglycemia than it was in lung cancer cells. CONCLUSION: A much lower k3 appears to be a rate-limiting factor for F-18 FDG accumulation in breast cancer, while the higher k3 in lung cancer is probably not rate limiting for F-18 FDG accumulation.

Magnetically-enhanced radionuclide therapy (MERiT): in vitro evaluation.

PURPOSE: Radionuclide therapy is a promising method for delivering radiation dose selectively to tumors. In situations where electron -emitters are used and the tumor is small relative to the maximum range of therapeutic electrons, these particles exit the tumor before delivering the maximum amounts of radiation dose. In this study, the method of magnetically constraining electrons to small tumors, known as magnetically -enhanced radionuclide therapy (MERiT), is explored using in vitro experiments. METHODS AND MATERIALS: The potential utility of MERiT was investigated by first measuring the reduction of number of electrons exiting a small sphere containing 90Y embedded in a block of plastic scintillator. Measurements of total energy deposited in the plastic scintillator made inside and outside a 7 Tesla magnetic field were compared. Furthermore, an experiment utilizing lymphoma cells of human origin was performed. Groups of cells were added to wells containing 90Y-labeled bovine serum albumin (and control groups containing no radioactivity) were placed either inside a 7 Tesla magnet or at a position where the magnetic field was minimal (essentially zero) for 18 hr. RESULTS: The presence of a 7 Tesla magnetic field reduced the amount of energy deposited in the scintillator by 16.63 +/- 1.05%. This demonstrates that the magnetic field constrains a large fraction of the emissions to the sphere and implies that normal tissues adjacent to radiotracer-avid tumors can be protected from radiation dose. Results from the cell culture experiment showed that the presence of a 7 Tesla magnetic field significantly (p < 0.005) reduced the number of viable cells remaining after treatment with non-specific 90Y-labeled bovine serum albumin by 11.7% compared to the appropriate control group (90Y treated, not exposed to magnetic field). CONCLUSIONS: These initial physical and biological studies indicate that magnetically-enhanced radionuclide therapy can be effective in increasing radiation absorbed dose to small tumors, consequently reducing radiation dose to surrounding normal structures.

Sustained improvement in growth velocity and recovery from suboptimal growth hormone (GH) secretion after treatment with human pituitary GH-releasing hormone-(1-44)-NH2.

The sustained effect of human pancreatic GH-releasing hormone [hpGHRH-(1-44)-NH2] on growth rate and GH secretory patterns was studied in 14 patients (10 males and 4 females; aged 10-16 yr; all Tanner stage I or II). Nine children had inadequate spontaneous GH secretion (ISGHS), while 5 had classic GH deficiency. Seven of 9 patients with ISGHS and 1 of 5 patients with GH deficiency were given 2 sc injections/day of 5 micrograms/kg GHRH for 2-3 months; the others received 5 pulses of GHRH (5 micrograms/kg BW.pulse) for 6 nights a week for 2-13 months, given every 3 h. Six of the nine ISGHS patients increased their growth velocity in response to GHRH therapy. These same six patients maintained an increased growth velocity for up to 24 months after GHRH was discontinued. The remaining three ISGHS patients did not show a significant growth response to GHRH administration. Neither a temporary nor a sustained growth response was correlated with spontaneous overnight GH secretion in these patients. In contrast, three of five classical GH deficiency patients exhibited increased growth velocity while undergoing GHRH therapy, but growth returned to preintervention rates upon discontinuation of treatment. The other two of the five classic GH deficiency patients failed to demonstrate any growth response to GHRH treatment. The increased growth velocity that was sustained for long intervals even after discontinuation of GHRH in ISGHS patients may indicate restoration of normal regulation of the hypothalamic-pituitary GH secretion axis.

Is there compensated hypothyroidism in infancy?

The state-mandated newborn thyroid screening program may uncover infants who exhibit normal thyroxine (T4) levels with various degrees of hyperthyrotropinemia. To elucidate further the thyroid status, the basal metabolic rate (BMR) of 10 infants (7 boys, 3 girls; aged 9 to 63 days) was studied by indirect calorimetry. They were clinically euthyroid and healthy with no evidence of overt biochemical hypothyroidism (low T4, high thyroid-stimulating hormone [TSH]). Confirmatory testing indicated that all infants had normal serum T4 levels for age (mean +/- SD: 10.3 +/- 3.2 micrograms/dL). However, serum TSH levels varied from 2.3 to 99.2 microU/mL. In 4 infants (2 boys, 2 girls) the BMR was low (38.1 +/- 4.1 kcal/kg per day), while the other 6 patients (5 boys, 1 girl) demonstrated BMRs within the normal range (49.6 +/- 1.9 kcal/kg per day, P less than .001). The serum TSH levels were above 7.0 microU/mL among those infants with a low BMR, whereas the serum TSH levels were always below 6.0 microU/mL among the normometabolic infants. All infants who had a low BMR received thyroid therapy and promptly became normometabolic (BMR: 48.7 +/- 1.0 kcal/kg per day) with suppression of TSH levels (3.2 +/- 1.3 microU/mL) within 3 weeks of therapy, while their serum T4 levels remained within the normal range. The observed normalization of BMR in parallel to reduction of TSH levels following thyroid replacement therapy strongly suggests that these patients demonstrated a hypometabolic state, despite normal serum T4 levels. Therefore, the assessment of BMR may help define subclinical hypothyroidism in infancy in conjunction with a close monitoring of TSH concentration.

Reported dietary intakes of patients with insulin-dependent diabetes mellitus: limitations of dietary recall.

Reported dietary intakes were assessed in young patients with insulin-dependent diabetes mellitus (IDDM). We studied 44 IDDM patients (24 males, 20 females, mean +/- SD age 13.2 +/- 4.5 yr) and compared them with 44 healthy age- and sex-matched control subjects. Estimated intakes from 24-h dietary recall were analyzed in relation to body weight and degree of diabetes control. The reported energy intake of the IDDM patients with greater than 120% ideal body weight (IBW) for height was 66, 59/88% (where X = geometric mean, L1 = lower confidence limit/L2 = upper confidence limit) of recommended daily allowance (RDA), whereas those with IBW less than 120% reported 90, 67/120% (p less than 0.01). Patients with increased weights in comparison with IBW had higher hemoglobin A1c (HbA1c) levels (11.9 +/- 2.7%) than those with weights more appropriate for IBW (9.7 +/- 2.4%, p less than 0.025). IDDM patients reported overconsumption of protein and fat, but their carbohydrate intake was low. Analysis of dietary recalls revealed high protein intake (X +/- SD, 20.0 +/- 5.0% of total calorie intake), especially in older (27 +/- 4%) compared with younger (19 +/- 2%-19 +/- 4%, p less than 0.01) patients. Proportions of carbohydrate, protein, and fat did not correlate with variations in body weight and/or HbA1c. The reported intake of protein per kilogram body weight was not significantly different between appropriate-weight and overweight IDDM patients. There was no significant difference in reported total energy intakes of IDDM patients compared with their healthy control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutritional dwarfing: a growth abnormality associated with reduced erythrocyte Na+,K(+)-ATPase activity.

To assess whether nonorganic nutritional dwarfing (ND) is accompanied by a biochemical adaptation to reduced nutrient intake, Na+,K(+)-ATPase activity of erythrocytes was examined. The study included 27 children with ND who demonstrated deteriorating linear growth and poor weight gain (caused by self-imposed dietary restrictions), 20 patients who initially exhibited ND growth patterns and subsequently experienced catch-up weight gain and growth after nutritional rehabilitation (NDR), and 32 normally growing children who had familial short stature and/or constitutional growth delay (F/CSS). Na+,K(+)-ATPase activity in erythrocytes was significantly lower in ND patients than in the NDR and F/CSS groups. Furthermore, Na+,K(+)-ATPase activity was positively correlated with incremental body weight gain. Na+,K(+)-ATPase concentrations did not differ significantly with regard to sex, chronological age, bone age, or pubertal status. These data suggest that the growth retardation of ND patients is associated with decreased erythrocyte Na+,K(+)-ATPase activity without other biochemical evidence of malnutrition.

Excess weight and precocious pubarche in children: alterations of the adrenocortical hormones.

In this paper we assess the qualitative and quantitative differences in adrenal function before and after adrenocorticotropic hormone (ACTH) stimulation between normal weight and overweight precocious pubarche (PP) patients. Twelve of the 22 PP patients had a normal body weight for height with linear growth and bone ages (BAs) that were appropriate for chronological age. The remaining 10 PP patients had body weights which were greater than 120% of ideal weight for height and body mass indices (BMIs), which were more than 125% of the ideal for age and sex. In six overweight patients, linear growth was accelerated and BAs were advanced beyond chronological age. All patients underwent an ACTH stimulation test where they received an intravenous bolus of 250 micrograms Cortrosyn. Blood samples were obtained at 0' and 60' for 17-OHProgesterone (17-OHP), 17-OHPregnenolone (17-OHPG), dehydroepiandrosterone (DHEA), androstenedione (A-dione), and cortisol levels. Results of the baseline and stimulated adrenal hormones in the normal weight children were found to be within reference range for normal Tanner I children. In contrast, two of the 10 overweight children were suspected of having congenital adrenal hyperplasia [one with 21-hydroxylase (21-OHase) deficiency, another with 3-betahydroxysteroid (3 beta ol) deficiency]. These two children were indistinguishable in their linear growth rate and degree of skeletal maturation from the other overweight children. In both patients the BA/chronological age and BA/height age (HA) ratios were within two standard deviations of the mean for the overweight patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A survey to determine the prevalence of abnormal growth patterns in adolescents from a suburban school district.

A longitudinal survey of 1017 (514 male, 503 female) school health records was undertaken to assess the prevalence of normal and abnormal growth patterns in adolescents attending a suburban upper middle class junior-senior high school. The vast majority (97.4% of the students) were growing and gaining weight at a steady rate, maintaining a similar percentile for height and weight throughout adolescence. However, 75% of these students had mild deficits or excesses of body weight for height, which also remained constant throughout adolescence. Approximately 10% of the students had a body weight deficit or excess for height greater than 20%. These students were growing along normal percentile patterns. This was true whether the student had short, normal, or tall stature. Only a minority (2.6%) had an abnormal growth pattern. There were 18 students who had deteriorating linear growth and had decelerated across one or two major percentile lines for height. Only eight students demonstrated accelerated growth characterized by progressive weight gain greater than 10 kg/year and crossing a major percentile line for weight.

Glycemic response in children with insulin-dependent diabetes mellitus after high- or low-glycemic-index breakfast.

To examine the effects of various carbohydrate foods on postprandial glycemia in diabetic children, we fed a mixed, isocaloric diet containing either high- or low-glycemic-index (GI) breakfast foods to 22 children with poorly controlled insulin-dependent diabetes mellitus (IDDM) and measured blood sugar response with and without adjustment of insulin doses. We found that IDDM children fed a high-GI meal showed a significantly higher serum glucose level than those fed a low-GI meal. However, such differences were not seen when the preprandial dose of regular insulin was adjusted to the amount of carbohydrate in feedings. Thus, as long as proper adjustment of insulin is made, the type of carbohydrate in a single mixed meal does not appear to have a significant effect on the postprandial glycemic response in children with long-standing poorly controlled IDDM.

Pituitary function assessment in short stature by a combined hormonal-stimulation test.

We utilized a combined, hormonal-stimulation test (CHST) using sequentially-administered insulin, thyrotropin-releasing hormone, gonadotropin-releasing hormone, and levodopa to assess 51 children with short stature and/or pathologic growth. Growth hormone, thyrotropin, gonadotropins, cortisol, and prolactin levels were sampled over two hours. All patients with appropriate predicted adult heights, delayed bone ages, and normal growth velocities of 4.0 cm/y or greater demonstrated normal pituitary responses. Two of 12 patients with predicted heights 2.5 SDs lower than target height and normal growth velocity demonstrated isolated growth hormone deficiency. Nine of 11 patients had a pathologic growth hormone deficiency or panhypopituitarism. Evaluation of pituitary function by combined sequential hormonal stimulation is fruitful in children with pathologic growth patterns but not in children with normal growth velocities and normal predicted adult height.

Pituitary-hypothalamic response in adolescents with growth failure due to fear of obesity.

Nine patients (4F, 5M) aged 12-17 years with "fear of obesity" were studied with a sequential stimulation test utilizing insulin, LRH, TRH, and L-dopa. The comparative groups were nine female with classic anorexia nervosa, five males with undifferentiated nutritional dwarfing, and nine children (1F, 8M) with constitutional growth delay. The serum TSH, glucose, cortisol, somatotropin, prolactin, LH, and FSH were sampled periodically over 2 hours. Basal T3, T4, transferrin, and Somatomedin-C levels were also obtained. The "fear of obesity" patients did not have any pituitary function changes that were unique. These patients, as well as the comparison groups, revealed a delayed TSH response in proportion to the weight deficit which, when expressed as an integrated response, correlated well to the weight deficit for height (P less than 0.001) and to the ability to recover from hypoglycemia (p less than 0.001). The Somatomedin-C level was low and correlated to the T3 level (p less than 0.05) and not correlated to the elevated Somatotropin levels. The pituitary response to combined stimulation in patients with fear of obesity was determined to be a component of the spectrum starting at normal and proceeding to the extreme undernutrition of anorexia nervosa. Pituitary responsiveness, therefore, changes not as a function of the etiology of the malnutrition, but simply as a function of its severity.

Premarin priming does not alter growth hormone release following exercise.

We evaluated the usefulness of premarin priming on exercise induced growth hormone release and the value of combining several growth hormone screening agents in a large population of prepubertal children. Two hundred five short healthy prepubertal children growing below the 5th percentile in height were studied. One hundred forty-four were screened with exercise following glucose ingestion, while 61 were primed with estrogen prior to glucose and exercise testing. Premarin priming did not significantly increase the number of our patients who responded to exercise nor to glucose; 86% and 88.5% of non-primed and primed patients, respectively, responded with a growth hormone increase greater than or equal to 8 ng/ml following exercise and glucose. Glucose loading alone was not associated with a high enough growth hormone rise to rule out growth hormone deficiency in most of our children. Age (less than or equal to 5 yr) was associated with lower post-exercise growth hormone levels and a higher failure rate to testing in both primed and non primed children. Premarin priming does not seem to alter the growth hormone releasing capacity to exercise of prepubertal children. The combined use of exercise, glucose loading and premarin priming in a single screening test does not improve on the results obtained by growth hormone exercise screening alone.

Breast feeding and insulin-dependent diabetes mellitus in children.

We have evaluated the hypothesis of a protective effect of human milk on the development of insulin dependent diabetes mellitus (IDDM). We studied the feeding histories of 95 diabetic children and compared them with controls consisting of their non-diabetic siblings and a pair matched group of nondiabetic peers of the same age, sex, geographical location, and social background. The incidence of breast feeding in diabetic children was 18%. This was similar to the control group. The duration of breast feedings was also similar among all three groups. There was no difference in the age of introduction of solid food between diabetic and nondiabetic children. Twice as many diabetic children, however, received soy containing formula in infancy as compared to control children. The mean age of onset of IDDM was not related to the type of feeding during infancy. The incidence of positive thyroid antibodies was two and one half times higher in formula-fed diabetic children than in breast-fed ones. In our studies we were unable to document any relationship between the history of breast feeding and subsequent development of IDDM in children.

Impaired somatomedin generation test in children with insulin-dependent diabetes mellitus.

Recent studies have suggested a partial block in somatomedin (SM) production or growth hormone (GH) action in IDDM. Twelve well-nourished diabetic children (9 males and 3 females with a mean age of 11.2 +/- 3.3 yr), six with an HbA1c of 7.9-11.2% (group A) and six with an HbA1c of 12.5-15.6% (group B), were studied as follows: the GH response after 100 micrograms of oral clonidine and the SM generation capacity after i.m. administration of 0.2 U/kg/dose of human growth hormone (hGH) for 4 days. Group B diabetic subjects had a significantly higher mean +/- SD GH increase after clonidine than did group A patients (delta of 17.4 +/- 4.9 versus 5.7 +/- 6.0 ng/ml, P less than 0.01); the basal GH of both groups were similar (1.6 +/- 0.7 versus 2.3 +/- 1.4 ng/ml). In contrast, the SM response to hGH was significantly decreased in group B children as compared with those in group A (delta of 0.3 +/- 0.3 versus 1.2 +/- 0.4 U/ml, P less than 0.01). The basal SM levels of both groups were normal for age. GH and SM correlated with HbA1c levels (r = +0.80, P less than 0.01; r = -0.79, P less than 0.01, respectively); there was no correlation with plasma and urine glucose or serum cholesterol, cortisol, and transferrin. Our data indicate a blunted SM response to hGH in group B diabetic subjects; this defect in SM generation is apparently not present in group A subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-dose oral clonidine. A simple and reliable growth hormone screening test for children.

We evaluated the efficacy and side effects of a low dose of oral clonidine hydrochloride on growth hormone release in 24 healthy short children; ten received 100 micrograms (group A) and 14 received 50 micrograms (group B). The mean +/- SD growth hormone peak at 60 minutes was 14.5 +/- 6.3 mg/mL in group A v 11.6 +/- 6.1 mg/mL in group B. Failure rate (growth hormone less than 10 mg/mL) was 10% in group A and 36% in group B. The drop in cortisol levels was similar in both groups. Blood pressure did not change significantly, and only mild somnolence was noted in all. A single dose of oral clonidine hydrochloride approximating 100 micrograms/sq m, followed by one blood sample after 60 minutes seems to be an effective and safe screening test for growth hormone deficiency in short children.