Successful use of recombinant human thyrotropin in the therapy of pediatric well-differentiated thyroid cancer.

Recombinant human TSH (rhTSH) is increasingly employed in stimulating radioiodine (131I) uptake in adults with well-differentiated thyroid cancer (WDTC) for diagnostic scanning, and preliminary evidence suggests that it may have a role in radioactive iodine therapy as well. However, the safety and efficacy of rhTSH in children have not been determined. We report a case of a 13-yr-old boy presenting with metastatic papillary thyroid cancer. After total thyroidectomy, his serum thyroglobulin (Tg) was 302 ng/ml (3.7-49.3) with negative antibodies. A diagnostic whole body scan (WBS) demonstrated multiple foci of uptake in the neck, thyroid bed and chest. His serum TSH only increased to 14.2 microU/ml (0.3-4.7) upon thyroid hormone withdrawal. Therefore, the patient was given 0.9 mg rhTSH every 24 h for two consecutive days and treated with 102 mCi 131I 24 h after the last rhTSH injection. Six months later, the patient was again conditioned with rhTSH and treated with an additional 150 mCi 131I. This treatment effectively reduced his tumor load with his most recent (10 months after the second ablation) serum Tg measuring 19.3 ng/ml. This case highlights the safety and effectiveness of rhTSH stimulated radioablation in pediatric WDTC, and proposes to invite controlled studies to further investigate pediatric rhTSH use, particularly in patients in whom thyroid hormone withdrawal is not a viable option.

Symptomatic Rathke's cleft cysts: a report of 24 cases.

We review the clinical, hormonal and imaging features of 24 consecutive patients with symptomatic Rathke's cleft cysts (RCCs), and assess the long-term effectiveness and complications of transsphenoidal cyst removal. Out of 250 consecutive patients, 24 (10%) underwent endonasal transsphenoidal surgery for RCC; 19 (79%) were women. Symptoms at presentation included headaches (83%), hyperprolactinemia (38%), central hypothyroidism (21%), galactorrhea (13%), diabetes insipidus (13%), IGF-1 deficiency (13%), central adrenal insufficiency (8%) and visual loss (8%). In total, 37% of women had irregular menses and 60% of men sexual dysfunction and hypogonadism. Two girls presented with precocious puberty. Cyst size varied from 7 to 25 mm. Fifteen (60%) had a suprasellar component. Initial and 3-month post-operative imaging revealed complete cyst resection in 23 of 24 patients. Headaches resolved in 65% of subjects and visual loss resolved in both patients who presented with this symptom. Of those presenting with endocrinopathy, 56% had improvement of at least one anterior pituitary axis; two subjects (8%), both with suprasellar RCC, developed a new hormone deficiency post-operatively and two sujects young girls, (8%) had RCC recurrence, one at 36 months after surgery, requiring a second operation, and the other had a small asymptomatic recurrence 6 months after surgery. In conclusion, RCC accounts for 10 % of surgically treated sellar and suprasellar masses. Headache, hyperprolactinemia, menstrual irregularities and sexual dysfunction are common presenting symptoms. Simple cyst removal via a transsphenoidal approach offers a safe and effective treatment. Cyst recurrence may be more common in children.

Long-term management and outcome of parathyroidectomy for sporadic primary multiple-gland disease.

HYPOTHESIS: For a specific subset of patients with sporadic primary multiple-gland parathyroid disease, subtotal parathyroidectomy results in long-term normocalcemia in the majority of patients, with a minimal complication rate. DESIGN: Retrospective analysis of outcomes in patients undergoing parathyroidectomy performed by a single surgeon (A.E.G.) between 1984 and 1999. SETTING: A multidisciplinary endocrine service based at a tertiary referral center. PATIENTS: Patients undergoing subtotal parathyroidectomy for primary hyperparathyroidism due to sporadic multiple-gland disease identified from a single surgeon's operative records (A.E.G.). MAIN OUTCOME MEASURES: Data analyzed included demographic factors, operative and pathologic findings, and postoperative and long-term clinical and laboratory results, including calcium and intact parathyroid hormone levels. RESULTS: Of 379 patients undergoing parathyroidectomy for hyperparathyroidism between 1984 and 1999, 49 (13%) had sporadic multiple-gland disease. Median preoperative calcium and intact parathyroid hormone (iPTH) levels were 2.7 mmol/L (10.8 mg/dL) and 11.79 pmol/L, respectively. Postoperative calcium and iPTH levels were available in 39 patients, and median values were 2.28 mmol/L (9.1 mg/dL) and 2.84 pmol/L, respectively. Long-term follow-up was available for 36 patients (73%), and duration ranged from 6 to 180 months (median, 44 months). Median calcium and iPTH levels at follow-up were 2.3 mmol/L (9.2 mg/dL) and 3.26 pmol/L, respectively, with 3 (8%) of 36 patients having evidence of persistent or recurrent hyperparathyroidism. No patient had biochemical evidence of hypoparathyroidism at long-term follow-up. Five patients (14%) had persistent elevated iPTH levels (range, 8.11-10.95 pmol/L) and normal calcium levels. CONCLUSIONS: Subtotal parathyroidectomy for sporadic primary multiple-gland disease resulted in a long-term normocalcemia rate of 92%, with minimal complications. Selective subtotal parathyroidectomy can yield excellent long-term results in patients with multiple-gland disease.

Beta cell function declines with age in glucose tolerant Caucasians.

OBJECTIVE: As type 2 diabetes results from an imbalance between insulin sensitivity and beta cell function, either or both may worsen with age. However, existing data are controversial on the effect of ageing on both insulin sensitivity and beta cell function. SUBJECTS AND DESIGN: We enrolled 149 healthy, glucose tolerant and normotensive Caucasians (age 35 +/- 1 years, body mass index 26.07 +/- 0.44 kg/m2, waist-hip ratio 0.842 +/- 0.009 cm/cm, mean +/- standard error). A cross-sectional study was designed to examine the impact of age on insulin sensitivity and beta cell function. Their beta cell function (percentage B [%B]) and insulin sensitivity (percentage S [%S]) were estimated using the homeostasis model assessment. RESULTS: Simple regression analysis revealed that %B declined with age (P = 0.008) while no relation was found between %S and age (P = 0.769). A stepwise regression analysis revealed that body mass index and diastolic blood pressure explained 14.7% of variation in %S, while age, waist-hip ratio, gender, and systolic blood pressure had no influence on %S. Age, body mass index and diastolic blood pressure together accounted for 21.7% of variation in %B, with age being an independent variable. CONCLUSIONS: In the present study, we showed that beta cell function declined with age at a rate of about 1% per year. In contrast, insulin sensitivity was not affected by ageing. Our observations suggest that the age-related decline in glucose tolerance is primarily related to the loss of beta-cell function.

Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report.

OBJECT: Recognition of pituitary hormonal insufficiencies after head injury and aneurysmal subarachnoid hemorrhage (SAH) may be important, especially given that hypopituitarism-related neurobehavioral problems are typically alleviated by hormone replacement. In this prospective study the authors sought to determine the rate and risk factors of pituitary dysfunction after head injury and SAH in patients at least 3 months after insult. METHODS: Patients underwent dynamic anterior and posterior pituitary function testing. Results of the tests were compared with those of 18 age-, sex-, and body mass index-matched healthy volunteers. The 22 head-injured patients included 18 men and four women (mean age 28+/-10 years at the time of injury) with initial Glasgow Coma Scale (GCS) scores of 3 to 15. Eight patients (36.4%) had a subnormal response in at least one hormonal axis. Four were growth hormone (GH) deficient. Five patients (four men, all with normal testosterone levels, and one woman with a low estradiol level) exhibited an inadequate gonadotroph response. One patient had both GH and thyrotroph deficiency and another had both GH deficiency and borderline cortisol deficiency. At the time of injury, all eight patients with pituitary dysfunction had an initial GCS score of 10 or less and, compared with the 14 patients without dysfunction, were more likely to have had diffuse swelling, seen on initial computerized tomography scans (p < 0.05), and to have sustained a hypotensive or hypoxic insult (p = 0.07). Of two patients with SAH who were studied (Hunt and Hess Grade IV) both had GH deficiency. CONCLUSIONS: From this preliminary study, some degree of hypopituitarism appears to occur in approximately 40% of patients with moderate or severe head injury, with GH and gonadotroph deficiencies being most common. A high degree of injury severity and secondary cerebral insults are likely risk factors for hypopituitarism. Pituitary dysfunction also occurs in patients with poor-grade aneurysms. Postacute pituitary function testing may be warranted in most patients with moderate or severe head injury, particularly those with diffuse brain swelling and those sustaining hypotensive or hypoxic insults. The neurobehavioral effects of GH replacement in patients suffering from head injury or SAH warrant further study.

Insulin sensitivity differs among ethnic groups with a compensatory response in beta-cell function.

OBJECTIVE: A drastic difference is evident in the prevalence of type 2 diabetes among ethnic groups. We examined the role of beta-cell function and insulin sensitivity in this disparity among 4 ethnic groups. RESEARCH DESIGN AND METHODS: beta-Cell function and insulin sensitivity were assessed in 77 healthy glucose-tolerant subjects using a hyperglycemic clamp (18 Asian-Americans, 9 African-Americans, 34 Caucasians, and 16 Mexican-Americans). RESULTS: A wide range of variation was evident in clinical features of the studied subjects. Insulin sensitivity index and the second-phase insulin response differed among the 4 groups (P = 0.0023 and P = 0.0082, respectively), whereas the first-phase insulin response was marginally different (P = 0.1090). Stepwise regression analysis revealed that ethnicity was an independent determinant for the insulin sensitivity index (P = 0.0014) after adjusting for sex, age, diastolic blood pressure, waist-to-hip ratio, and BMI. Also, a compensatory response of beta-cell function was observed among the ethnic groups. CONCLUSIONS: In this study, we observed a drastic difference in insulin sensitivity among the different ethnic groups and observed that their beta-cell function compensates for the prevailing insulin sensitivity. The difference in the prevalence of abnormal glucose tolerance in different ethnic groups could be a result of differences in insulin sensitivity

Amyloid goiter in a case of systemic amyloidosis secondary to ankylosing spondylitis.

Infiltrative diseases of the thyroid include systemic sclerosis, hemochromatosis, sarcoidosis, chondrocalcinosis and amyloidosis. Only rarely does thyroid amyloidosis result in clinically palpable goiter. Classically, amyloidosis is associated with tuberculosis, rheumatoid arthritis, multiple myeloma or inflammatory bowel disease. Only rarely does clinical amyloidosis develop in the setting of ankylosing spondylitis. We describe a case of amyloid goiter in a patient with ankylosing spondylitis-associated amyloidosis.

Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer.

We have cloned and characterized a 620-bp fragment of DNA that flanks 5' of the prostate-specific antigen (PSA) gene from a prostate cancer patient. Using DNA transfection, the efficacy of this putative promoter in regulating gene expression was quantitated in several prostate and nonprostate tissue cell lines. Our results demonstrated that the 620-dp DNA fragment actively drives gene expression in LNCaP, a PSA-producing prostate tumor cell line. No promoter activity was detected in the non-PSA-producing prostate tumor lines, DU145 and PC-3, nor in a renal (R11) or breast (MCF-7) cancer cell line. Furthermore, the promoter activity could be regulated in vitro by androgen stimulation. Dihydrotestosterone (DHT) concentrations between 3 and 30 nM induced the highest promoter activity in the transfected LNCaP cells, which parallels the expression profile of the androgen receptor in LNCaP cells. In addition, our PSA promoter exhibited competitive inhibition of the endogenous genomic PSA promoter in transfected LNCaP cells, suggesting that prostate cell-specific DNA-binding proteins are required to activate the PSA promoter. increased its potency four- to five-fold while retaining tissue specificity. Our data suggest that a strong tissue-specific negative regulatory element capable of overriding the nonspecific CMV promoter is present in the PSA promoter and confers its tissue specificity. The use of a highly specific promoter-driven gene vector will allow selective expression of therapeutic genes within PSA-producing prostate cancer cells, providing a unique strategy for prostate cancer gene therapy.

Gene therapy: principles and potential.

Gene therapy is a new and provocative means of treating human malignancy. Insight into the mechanisms of growth and growth regulation within cancer cells has offered multiple potential methods for genetic intervention. The application of gene therapy to prostate cancer is in its infancy. The development of both adenoviral and retroviral replication deficient vectors has provided the ability consistently to transfer genes into cancer cells. Although the ideal gene for transfer has not yet been clearly identified, many genes capable of altering the biological behaviour of prostate cancer exist. Selection of the appropriate gene is highly dependent on the desired therapeutic outcome. A gene therapy strategy, whether dependent on ex vivo or in vivo transfection, must ultimately be tailored to meet the specific needs of the disease to be treated. The potential to treat locally confined disease, preventing subsequent metastasis, or widespread metastatic disease exists. The ultimate success of a prostate cancer gene therapy strategy will rely on comprehensive investigation of the biology of the tumour and careful planning of an effective intervention.

Cysteine scanning mutagenesis of the N-terminal 32 amino acid residues in the lactose permease of Escherichia coli.

Using a functional lactose permease mutant devoid of Cys residues (C-less permease), each amino acid residue in the hydrophilic N-terminus and the first putative transmembrane helix was systematically replaced with Cys (from Tyr-2 to Trp-33). Twenty-three of 32 mutants exhibit high lactose accumulation (70-100% or more of C-less), and an additional 8 mutants accumulate to lower but highly significant levels. Surprisingly, Cys replacement for Gly-24 or Tyr-26 yields fully active permease molecules, and permease with Cys in place of Pro-28 also exhibits significant transport activity, although previous mutagenesis studies on these residues suggested that they may be required for lactose transport. As expected, Cys replacement for Pro-31 completely inactivates, in agreement with previous findings indicating that "helix-breaking" propensity at this position is necessary for full activity (Consler TG, Tsolas O, Kaback HR, 1991, Biochemistry 30:1291-1297). Twenty-nine mutants are present in the membrane in amounts comparable to C-less permease, whereas membrane levels of mutants Tyr-3-->Cys and Phe-12-->Cys are slightly reduced, as judged by immunological techniques. Dramatically, mutant Phe-9-->Cys is hardly detectable when expressed from the lac promoter/operator at a relatively low rate, but is present in the membrane in a stable form when expressed at a high rate from the T7 promoter. Finally, studies with N-ethylmalemide show that 6 Cys-replacement mutants that cluster at the C-terminal end of putative helix I are inactivated significantly.(ABSTRACT TRUNCATED AT 250 WORDS)