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Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 37 records · Page 2Linked to original sources
PubMed2002

Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil.

OBJECTIVE: Combination chemotherapy with the two agents streptozotocin (SZT), which is a nitrosurea, and 5-fluorouracil (5-FU), an alkylating agent, has a long-established role in the treatment of neuroendocrine tumours; however, it is often accompanied by considerable toxicity, and it has not been assessed in a comparative manner with other current chemotherapy regimens. In order to assess the therapeutic response and adverse effects using an alternative nitrosurea, lomustine (CCNU), which has a different side-effect profile, in combination with 5-FU, we have reviewed all patients with neuroendocrine tumours who received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with metastatic neuroendocrine tumours who received treatment with the combination of CCNU and 5-FU, and who were followed up according to a defined protocol in a given time frame. PATIENTS: Thirty-one patients with metastatic neuroendocrine tumours (18 with carcinoid tumours, five islet-cell tumours, five chromaffin-cell tumours and three medullary carcinoma of the thyroid) treated with the combination of CCNU and 5-FU, and when necessary additional therapy, over a 22-year period, were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after chemotherapy with the combination of CCNU and 5-FU over a median follow-up duration of 25 months (range 9-348 months) were recorded. Of the 31 patients (16 males; median age 52 years, range 20-86 years), eight (four males; median age 61 years, range 30-74 years) were treated with the combination of CCNU and 5-FU alone (Group 1), whereas the other 23 patients (12 males; median age 47 years, range 20-86 years) received additional therapy with other chemotherapeutic regimens, somatostatin analogues, alpha-interferon or radiolabelled meta-iodobenzylguanidine (131I-MIBG) therapy (Group 2). RESULTS: A total of 121 therapeutic cycles was administered (mean 3.9, range 1-14 cycles). None of the patients obtained a complete tumour response. A partial tumour response (not a complete but a 50% or greater reduction of all measurable tumour) was seen in six out of the 29 patients (21%) (four out of eight in Group 1 and two out of 21 in Group 2, respectively). There was no tumour progression in eight out of the 29 patients (27.5%) (one out of eight in Group 1 and seven out of 21 in Group 2, respectively). The median survival over the period of the study was 48 months (95% confidence interval, CI, 22-74 months). The overall 5-year survival rate was 42% (95% CI, 17-67%) for all patients and 50% (95% CI, 18-83%) for the carcinoid group alone, according to Kaplan-Meier analysis. A complete or partial symptomatic response was obtained in 12 out of 27 (44%) patients who presented with symptoms (four out of eight in Group 1 and eight out 19 in Group 2, respectively) and a complete or partial hormonal response in eight out of 19 patients (42.1%) who presented with hormonally active disease (two out of four in Group 1 and six out of 15 in Group 2, respectively). Nine out of the 15 (60%) patients with carcinoid tumours who presented with symptoms obtained a symptomatic response, five out of 10 patients (50%) a hormonal response, and four out of 16 (25%) patients a partial tumoural response, respectively. The combination of CCNU and 5-FU was safe and well tolerated. Serious side-effects necessitating the termination of CCNU and 5-FU were seen only in two patients, and mainly consisted of reversible bone marrow suppression. No chemotherapy-related death was recorded. CONCLUSIONS: Chemotherapy with CCNU and 5-FU, either alone or in combination with other therapeutic modalities, produces considerable symptomatic and hormonal improvement and moderate tumour regression/stabilization according to currently accepted WHO criteria, particularly in patients with metastatic gastroenteropancreatic neuroendocrine tumours with minimal adverse effects. However, long-term survival was still relatively poor. It may therefore be a valuable additional therapl was still relatively poor. It may therefore be a valuable additional therapeutic option, particularly for well-differentiated carcinoid and islet-cell tumours, but mainly reserved for when there is no response or progression of the disease after currently available first-line treatment with somatostatin analogues or radiopharmaceuticals.

Adult↗
PubMed2002

Suprasellar germ cell tumours: specific problems and the evolution of optimal management with a combined chemoradiotherapy regimen.

OBJECTIVE: Suprasellar germ cell tumours are rare, and there are few series of patients outlining the problems in diagnosis and management, and providing clear guidelines for optimal therapy. We have therefore reviewed our own series of 11 such patients who were managed in a joint endocrinology/clinical oncology setting. PATIENTS AND DESIGN: A retrospective case review assessment of all patients seen within a given time. Clinical, biochemical and radiological findings were reviewed, the types of therapy administered noted, and the responses to treatment analysed. RESULTS: In the years 1977-2001, 11 patients with suprasellar (SS) germ cell tumours (GCT) were seen (germinomatous : nongerminomatous = 8 : 3). SSGCT had an approximately equal sex incidence (M : F, 6 : 5), in contrast to pineal tumours, the commonest site of origin of intracranial GCT and which occur predominantly in men. The median age at presentation was 20 years (range 6-49 years) with a median duration of symptoms before diagnosis of 17 months (range 1-35 months). Polyuria was the commonest presenting symptom (10 patients). Diabetes insipidus occurred in all patients, as did partial or complete anterior pituitary failure. Visual failure was present in 55% of cases. Anorexia, weight loss and disturbed thirst sensation were also common. Positron emission tomography scanning was occasionally useful in the evaluation of suprasellar tumours/pituitary stalk lesions deemed too risky to biopsy. A "central nervous system-friendly" chemoradiotherapy regimen comprising vincristine, etoposide and carboplatin and differential daily dose irradiation, usually administered using a partial transmission block technique, produced a 5-year survival of 100% with low morbidity. Treatment did not correct previously abnormal endocrine function although it did improve vision in three of six patients. CONCLUSIONS: We therefore emphasize the use of techniques other than biopsy in the diagnosis of these patients, note the problems in the management of their fluid control, and highlight the favourable response to a combined chemotherapy-radiotherapy protocol.

Adolescent↗
PubMed2002

Pancreatic lesions in von Hippel-Lindau disease.

OBJECTIVE: Von Hippel-Lindau disease is an inherited neoplasia syndrome. The main endocrine manifestations are phaeochromocytoma and paraganglioma. The presence of pancreatic disease has also been variably reported. This study was undertaken to describe the prevalence, nature, natural history and clinical associations of pancreatic lesions in von Hippel-Lindau disease. PATIENTS AND DESIGN: A retrospective analysis of the case notes of 17 consecutive patients. Average duration of follow-up was 5.5 years. Clinical, biochemical, genetic and radiological testing was routinely performed. RESULTS: Eleven (64.7%) patients had pancreatic lesions either on computed tomography or magnetic resonance imaging. Serous microcystic adenomas and multiple cysts were the commonest findings, but solid lesions were also found. The commonest clinical association was diabetes mellitus in patients with extensive serous microcystic adenomas. None of the pancreatic lesions showed evidence of biochemical function. All patients with pancreatic lesions also had renal lesions. Mutations were found at several points in the gene and there was no apparent association between pancreatic lesions and a particular mutation. CONCLUSIONS: Pancreatic lesions are very common in von Hippel-Lindau disease and all patients had coexisting renal lesions. The main clinical correlate was diabetes mellitus, but otherwise the lesions were clinically and biochemically silent.

Adenoma↗
PubMed2002

Growth in disorders of adrenal hyperfunction.

Growth is disturbed by adrenal hypersecretion of androgens or cortisol. Androgen excess in virilizing adrenal tumours causes advanced growth and bone age. In 9 girls with virilizing tumours, mean heights at diagnosis and final heights were 1.23 +/- 0.42 and 1.3 +/- 0.37 SDS respectively. In poorly controlled CAH, excess androgens cause early epiphyseal fusion and adult short stature. Increased growth occurs only after 18 months of age, even in untreated CAH, i.e. hydrocortisone >10 mg/m(2)/day is not generally required and may suppress infantile growth, affecting childhood and adult height. Growth was studied in 19 patients, aged 6.4-17.8 years, with Cushing's disease (CD). At diagnosis, mean height SDS was -1.81 (1.2 to -4.17), 53% < -1.8 SDS, height velocity in 6 was 0.9-3.8 cm/year and mean BMI SDS 2.29 (0.7-5.06). From 1983 to 2001, CD was cured in 18 patients (61%) by transsphenoidal surgery (TSS) alone and 39% by TSS plus pituitary irradiation (RT). In 13 patients, growth hormone (GH) was assessed by ITT/glucagons at 1-108 months after cure. Four had severe GH deficiency (<9 mU/l), 7 subnormal (10-29 mU/l) and 2 normal (>30 mU/l) GH status. Subnormal GH was present in 7 subjects >2 years after TSS or RT cure. In 10 subjects, aged 12.9 +/- 3.4 years, growth after cure was studied for 9.1 +/- 5.0 years. Nine had no catch-up growth in the interval of 0.3-1.1 years after cure (mean HV 5.3 +/- 2.4 cm/year). All these had GH deficiency peak GH 0.5-20.9 mU/l, and received hGH 2.7 mg/m(2)/week, 3 with GnRHa. All 10 showed long-term catch-up growth with mean delta SDS at diagnosis (Ht SDS-target Ht SDS) -1.72 +/- 1.26 improving to -0.83 +/- 1.08 (p = 0.0005) at latest of final Ht. At diagnosis, virilization was present in 82% of 17 patients with CD. Mean SDS values of serum androstenedione, DHEA-S and testosterone were normal, i.e. 0.72 (-2.9 to 3.0), -0.8 (6.0 to 2.2), 0.7 (-7.9 to 9.5) respectively, whereas SHBG was reduced at -2.1 (-5.3 to 1.2), increasing free androgen levels. Bone age (BA) was delayed (mean 1.46 years) in 14/16 patients, suggesting cortisol excess contributed more then androgen effect to skeletal maturation. In conclusion, most paediatric patients with CD had subnormal linear growth with delayed BA. After cure by TSS or pituitary irradiation, GH deficiency was frequent and persisted for many years. Treatment with hGH induced significant long-term catch-up growth leading to reasonable final height.

Adolescent↗
PubMed2002

Neurosurgical treatment of Nelson's syndrome.

Total bilateral adrenalectomy remains the definitive procedure for cure in Cushing's disease. It is complicated by the development of Nelson's syndrome, the treatment of which remains troublesome. We report the long-term follow-up, median 17 yr (range, 8-22 yr), of 13 patients (3 males and 10 females) treated with pituitary surgery for Nelson's syndrome at a median age of 35 yr (range, 21-67 yr). The presence of a pituitary mass lesion necessitated neurosurgery in all. Preoperatively, the median plasma ACTH level was 664 pmol/liter (range, 92-3665 pmol/liter); this fell to 29 pmol/liter (range, <2 to 1124 pmol/liter) postoperatively (P < 0.0005). Cutaneous hyperpigmentation was reduced in all and resolved in 11 patients. The pituitary tumor bulk was clearly reduced in 12 patients. There was no perioperative mortality. No patient developed a visual field defect attributable to surgery. New anterior pituitary hormone deficiency occurred in seven patients, and permanent diabetes insipidus occurred in five patients. At latest follow-up, the median plasma ACTH is 73 pmol/liter (range, <2 to 7759 pmol/liter); six patients have levels of less than 44 pmol/liter and also have a resolution of their pigmentation and no evidence of a recurrence of a pituitary mass lesion. We conclude that pituitary surgery is an efficacious treatment for mass lesions associated with Nelson's syndrome, has long-term benefit with minimal side effects, and must be considered in the management of this distressing complication.

Adrenocorticotropic Hormone↗
PubMed2002

Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

The CRH test is in widespread use for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Despite the greater availability worldwide of human-sequence CRH (hCRH), there are no large series reporting the response criteria that best discriminate between Cushing's disease (CD) and the ectopic ACTH syndrome (EC) when using hCRH, rather than ovine-sequence CRH. We have, therefore, analyzed retrospectively the serum cortisol and plasma ACTH responses to hCRH in patients with ACTH-dependent CS, to develop response criteria that best discriminate between CD and EC. One hundred fifteen consecutive patients with proven ACTH-dependent CS were studied: 101 with CD (78 females; mean age, 40 yr; range, 10-73) and 14 with EC (7 females; mean age, 46 yr; range, 32-69). The response to hCRH was also studied in 30 normal volunteers (NVs; mean age, 29 yr; range, 20-44) with no clinical evidence of CS, and the results were compared. Following basal sampling at -15 and 0 min, hCRH (100 microg iv) was administered via an indwelling forearm cannula at 0900 h and serum cortisol and ACTH were measured at 15-min intervals for 2 h. The mean basal, peak, incremental, and percentage change in the serum cortisol and ACTH at all time points, and combination of time points, were calculated and analyzed to establish the best criteria to discriminate between CD and EC, and also between CD and NVs. The mean serum cortisol concentration in samples obtained at 15 and 30 min after CRH increased by at least 14% above the mean basal in 85 of 100 patients with CD, but in none with EC, giving a sensitivity of 85% at a specificity set at 100%. In contrast, the best plasma ACTH response of a rise of 105%, calculated from the maximal rise, gave only 70% sensitivity at 100% specificity. In the NVs, the maximum cortisol at the mean 15+30 min time point was 615 nmol/liter. Using the 15 and 30 min time points as the reference point, 71 of 100 patients with CD had a rise of serum cortisol greater than 14% and also showed an absolute cortisol level more than 615 nmol/liter. Serum cortisol responses to hCRH can be used to suggest the diagnosis of CD in the majority of patients with this condition, but it should only be used in conjunction with other biochemical and imaging modalities in establishing this important diagnosis. The measurement of plasma ACTH was less helpful in making this distinction, although it may have additional value in excluding ACTH-independent causes of CS. Although we believe that bilateral inferior petrosal sinus sampling remains the single most useful test in discriminating CD from EC in patients with ACTH-dependent CS, hCRH offers rapid diagnostic information and is a useful adjunctive test in establishing the presence of a possible ectopic source.

ACTH Syndrome, Ectopic↗
PubMed2002

Ocular metastases secondary to carcinoid tumors: the utility of imaging with [(123)I]meta-iodobenzylguanidine and [(111)In]DTPA pentetreotide.

Ocular metastases from carcinoid tumors are considered rare. They can be the primary presentation of a carcinoid tumor or develop during the course of the disease. The extent of distant metastases from carcinoid tumors correlates with poor prognosis and survival; early detection of metastasis may change the overall management. Radiopharmaceutical-labeled imaging techniques have been widely applied for the detection and localization of such lesions based on isotope uptake by neuroendocrine tumors. Routine application of these imaging modalities may reveal previously unsuspected lesions and may also be used to help stage the disease and to identify patients who may be treated with radiopharmaceuticals. Of 40 patients with carcinoid tumors reviewed in our department since we started routine scanning, we identified 6 (15%) who demonstrated ocular metastases: 5 with obvious lesions and 1 with presumed metastasis according to the results of nucleotide scanning. All 6 were negative on screening with [(123)I]meta-iodobenzylguanidine, whereas 3 of 4 who were screened with [(111)In]octreotide showed positive uptake. All patients responded well to radiotherapy and chemotherapy and did not require surgical treatment. The orbit and its contents appear to be a common site for carcinoid metastasis, and radiopharmaceutical imaging with labeled octreotide is useful in identifying many of these lesions.

3-Iodobenzylguanidine↗
PubMed2002

A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal.

Standard medical therapy for patients with acromegaly includes somatostatin analogs. Owing to the widespread expression of somatostatin receptors, these may be associated with unwanted effects, such as altered glucose tolerance and impaired gut hormone release. Pegvisomant is a novel pegylated GH analog that competes with wild-type GH for GH-receptor binding sites but contains a position 120, amino acid substitution that prevents functional GH receptor dimerization, a known prerequisite for GH signal transduction and generation of IGF-I. We have studied the short-term effects of these two therapies (pegvisomant 20 mg/d for 7 d and octreotide 50 microg thrice daily for 7 d) on glucose tolerance and stimulated gut hormone release in six healthy male volunteers in an open-label, random-order, cross-over study. Subjects were assessed at baseline (oral glucose tolerance test and standard mixed meal) and on d 6 and 7 of each therapy with a minimum washout of 2 wk between treatments. Area under the curve and peak responses were analyzed using one-way repeated-measures ANOVA (on ranks where appropriate). Pegvisomant had no effect on glucose tolerance or stimulated gut hormone response during an oral glucose tolerance test and a standard meal. In contrast, octreotide significantly increased fasting plasma glucose, lowered fasting plasma insulin, and led to deterioration in glucose tolerance; three subjects developed impaired glucose tolerance and one diabetes mellitus by World Health Organization criteria. Octreotide significantly impaired stimulated release of cholecystokinin, gastrin, insulin, and pancreatic polypeptide. In conclusion, pegvisomant, unlike octreotide, is not associated with deterioration in glucose tolerance and impairment of stimulated gut hormone release in normal males.

Administration, Oral↗
PubMed2002

Growth hormone replacement does not increase serum prostate-specific antigen in hypopituitary men over 50 years.

OBJECTIVE: Epidemiological studies have shown an increased risk for prostate carcinoma in men with serum IGF-I in the upper part of the age-related reference range. Recombinant human GH (rhGH) is widely used in patients with GH deficiency, usually raising the serum IGF-I levels into the normal range: safety surveillance is therefore mandatory, with particular regard to neoplasia. The aim was to examine whether rhGH replacement in hypopituitary adults is associated with changes in serum prostate-specific antigen (PSA) as a surrogate marker of changes in prostatic growth. DESIGN AND METHODS: A prospective longitudinal study was used with a median follow-up of 22 (range 2.5-32) months, in which 41 men aged over 50 years with adult onset hypopituitarism and GH deficiency during rhGH replacement were examined. Serum PSA and IGF-I were measured at baseline and at latest follow-up. RESULTS: Mean serum PSA remained unchanged during rhGH replacement, with a median follow-up of 2 years. No correlation was found between the individual changes in serum IGF-I and changes in serum PSA. CONCLUSIONS: These data are reassuring thus far regarding the safety of GH replacement in relation to the prostate in this patient group.

Aged↗
PubMed2001

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.

BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.

Acromegaly↗
PubMed2001

Clinical use of a growth hormone receptor antagonist in the treatment of acromegaly.

The elucidation of the mechanisms by which growth hormone (GH) interacts with its receptor has facilitated the design of compounds that function as GH-receptor antagonists. One such compound, B2036, has been conjugated to polyethylene glycol to produce a drug, pegvisomant, that has a powerful ability to lower circulating concentrations of insulin-like growth factor I (IGF-I), the principal mediator of GH action, in patients with acromegaly and to improve the symptoms and signs associated with GH excess. This article describes the mechanism of action of GH-receptor antagonists, reviews the preclinical and clinical data on the use of pegvisomant and discusses some of the challenges that lie ahead in judging the efficacy of a treatment that, unlike established therapies for acromegaly, does not aim to modify the underlying cause of acromegaly, namely excess GH secretion, but aims to lower serum IGF-I levels to normal.

Acromegaly↗
PubMed2001

Increased levels of insulin-like growth factor binding protein-2 in sera and tumours from patients with colonic neoplasia with and without acromegaly.

OBJECTIVE: Patients with acromegaly are at increased risk of developing colorectal carcinoma and premalignant tubulovillous adenoma. The pathogenesis of these neoplasms could involve a stimulatory effect of serum growth factors on colonic epithelial cell proliferation. The aim of this study was to evaluate changes in (1) serum IGF-I, IGF-II, IGFBP-3 and IGFBP-2 and (2) changes in local expression of IGFBPs and p53 in colonic epithelium in patients with colonic neoplasia with and without acromegaly. DESIGN: A cross-sectional retrospective study was performed. Fasting serum samples were obtained at the time of colonoscopy for patients with acromegaly and at the time of surgery for patients with colonic neoplasia without acromegaly. MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured using specific immunoassays. Tissue expression of IGFBP-2, IGFBP-3 and p53 status were determined by immunohistochemistry. PATIENTS: Group 1: 26 age- and sex-matched control subjects (range 40-69 years); group 2: 18 patients with acromegaly without colonic neoplasia (range 39-68 years); group 3: 18 patients with acromegaly and colonic neoplasia (range 41-74 years, 11 = adenoma, seven = carcinoma); group 4: 19 patients with colonic neoplasia without endocrine disease (range 43-91 years, four = adenoma, 15 = carcinoma). Immunohistochemical staining of colonic biopsies was performed for IGFBP-2, IGFBP-3 and p53 in groups 3 and 4. RESULTS: Mean serum IGF-I and IGFBP-3 levels were significantly elevated in group 2 (371 +/- 131 microg/l and 6.5 +/- 1.8 mg/l, respectively) and group 3 (379 +/- 174 microg/l and 5.8 +/- 1.6 mg/l, respectively), and significantly reduced in group 4 (103 +/- 36 microg/l and 2.4 +/- 1 mg/l) compared to controls (165 +/- 40 microg/l and 4.7 +/- 1 mg/l; P < 0.0001, P < 0.001, respectively). However, median serum IGFBP-2 levels were significantly elevated in group 3 (P < 0.01) and group 4 (P < 0.0001). Immunostaining for IGFBP-2 showed strong areas of immunoreactivity in the cytoplasm of malignant colonic epithelium compared to benign epithelium. IGFBP-3 immunostaining showed strong areas of immunoreactivity in the cytoplasm and in the nucleus of malignant and benign colonic epithelium compared to the normal epithelium. Nuclear staining for p53 was observed in three patients from group 3 (two carcinoma, one adenoma) and four patients from group 4 (all carcinoma). CONCLUSION: Our results describe changes in IGFBP-2 expression in colonic neoplasia in patients with and without acromegaly, which suggest that this binding protein may regulate local bioavailability of IGF, which in turn could modulate colonic cell proliferation and/or differentiation.

Acromegaly↗
PubMed2001

The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study.

OBJECTIVES: The objectives of this study were to investigate the effects of GH replacement therapy in hypopituitary adults with growth hormone deficiency (GHD) on activation of bone remodelling during dose titration and on BMD over a median of 58 months of continuous therapy. STUDY DESIGN: Open label study in adult patients with GHD. rhGH was commenced at dose of 0.8 IU subcutaneously daily (0.4 IU if hypertensive or glucose tolerance impaired) with subsequent dose titration based on 2 weekly measurement of serum IGF-I until levels reached the target range (between the median and upper end of the age related reference range). In patients previously commenced on GH using weight based regimens the dose of GH was adjusted during clinical follow-up in order to maintain serum IGF-I in the target range. PATIENTS: Initial effects of GH on bone remodelling during dose titration were studied in 17 patients (8F). Long-term effects of GH were determined in a separate group of 13 GHD adults (6F) over a median period of 58 months (range 44-72). MEASUREMENTS: Osteoblastic activity was estimated by measuring serum bone specific alkaline phosphatase (S-BAP). BMD was determined at both lumbar spine (L2-L4) and femoral neck by dual energy X-ray absorptiometry (DEXA). RESULTS: During dose titration a significant increment in S-BAP was observed by 10 weeks in females but occurred later in males (12-26 weeks). In the long term treatment group there was a significant increment in S-BAP compared to baseline (P = 0.013) after 6 months GH treatment. After long-term GH treatment (median 58 months) S-BAP levels decreased and were no longer statistically significantly different from baseline at the end of the study period. A similar response was observed in male and female patients. There were no significant differences in baseline BMD between male and female patients at either lumbar spine or femoral neck in the long term treatment group. No significant changes were observed in BMD after 6 months GH treatment in either lumbar spine or femoral neck but BMD increased over the remainder of the study at both sites (P = 0.023 and P = 0.03 respectively). When analysed by gender male patients showed a clear positive change in BMD after longer-term replacement in both lumbar spine and femoral neck (P = 0.01 and P = 0.02 respectively) but female patients showed no significant changes. Qualitatively similar results were observed when analysing changes in BMD expressed as Z scores. CONCLUSION: This study demonstrates an earlier onset of GH activation of bone remodelling as reflected by S-BAP in females compared to males and confirms that long-term GH treatment in hypopituitary adults with GH deficiency increases or preserves BMD both at lumbar spine and femoral neck. However male patients seem to derive the greater benefits in BMD from long-term GH replacement; in females BMD appears simply to be stabilized rather than increased. This constitutes a genuine gender difference in susceptibility given that serum IGF-I was in the upper part of the reference range in all subjects.

Adult↗
PubMed2001

The release of leptin and its effect on hormone release from human pituitary adenomas.

BACKGROUND: Leptin is the protein product of the obese gene, known to play an important role in body energy balance. The leptin receptor exists in numerous isoforms, the long isoform being the major form involved in signal transduction. Leptin expression has recently been demonstrated in the human pituitary, both in normal tissue and in pituitary adenomas. The long isoform of the leptin receptor has also been shown to be present in pituitary adenomas; however, contrasting results have been obtained regarding its expression in the normal human pituitary. AIM: The aim of this study was (i) to investigate the presence and pattern of distribution of leptin mRNA and the long isoform of its receptor mRNA in the normal pituitary and in different types of pituitary adenomas with RT-PCR; (ii) to study leptin secretion from human pituitary tumours in culture and (iii) to assess in vitro pituitary hormone release following stimulation with human leptin. RESULTS: Leptin receptor long isoform expression was detected in 2/4 GH-secreting adenomas, 12/17 non-functioning adenomas, 5/9 ACTH-secreting adenomas, 1/2 prolactinomas, 2/2 FSH-secreting adenomas and 5/5 normal pituitaries. The receptor long isoform did not segregate with any particular tumour type, and varying levels of expression were detected between the tissues studied. Leptin mRNA was detected at a low level of expression in 2/7 GH-secreting adenomas, 9/14 non-functioning adenomas, 2/3 ACTH-secreting adenomas, 1/3 prolactinomas and 1/3 FSH-secreting adenomas. We were unable to detect leptin mRNA in any of the five normal pituitaries removed at autopsy; however, immunostaining of a non-tumorous pituitary adjacent to an adenoma removed at transsphenoidal surgery showed scattered leptin positive cells. Culture of pituitary adenomas showed that 16/47 released leptin into the incubation media. Leptin release did not correlate with tumour type or with any of the other pituitary hormones released. In vitro leptin stimulation of pituitary tumours caused stimulation of FSH and alpha-subunit secretion from a non-functioning adenoma and TSH secretion from a somatotroph adenoma. CONCLUSION: We conclude that not only is leptin stored within the pituitary, but it may also be released from pituitary cells and modulate other pituitary hormone secretion. Pituitary leptin may therefore be a novel paracrine regulator of pituitary function.

Adenoma↗
PubMed2001

Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG].

OBJECTIVE: Meta-iodo-benzyl-guanidine labelled with 131-iodine [(131)I-mIBG] has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non-catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of (131)I-mIBG, we have reviewed all patients who had received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with (131)I-mIBG and were followed-up according to a defined protocol in a given time frame. PATIENTS: Thirty-seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with (131)I-mIBG over a 15-year period were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after (131)I-mIBG therapy over a median follow-up duration of 32 months (range 5-180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18-81 years), 15 were treated with (131)I-mIBG alone whereas the other 22 received additional therapy. RESULTS: A total of 116 therapeutic (131)I-mIBG doses were administered [mean cumulative dose 592 mCi (21.9 GBq); range 200-1592 mCi (7.4-58.9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with (131)I-mIBG alone and 84% who received additional therapy showed stable disease over the period of follow-up. Overall survival during the period of the study was 71%. The overall 5-year survival rate was 85% (95% confidence interval, 72-99%) for all patients and 78% (95% confidence interval, 55-100%) for the carcinoid group alone, according to Kaplan-Meier analysis. Symptomatic control was achieved in all the patients treated with (131)I-mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. (131)I-mIBG therapy was safe and well tolerated. Serious side-effects necessitating the termination of (131)I-mIBG therapy were seen in only 2 of our patients. CONCLUSIONS: (131)I-mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.

3-Iodobenzylguanidine↗
PubMed2001

The role of 123I-diagnostic imaging in the follow-up of patients with differentiated thyroid carcinoma as compared to 131I-scanning: avoidance of negative therapeutic uptake due to stunning.

OBJECTIVE: Some patients with relapsed differentiated thyroid cancer may show rising thyroglobulin (Tg) levels despite a lack of 131I uptake on routine whole body imaging. A significant proportion of these patients, after therapy doses of 131I, may demonstrate positive 131I uptake with a subsequent fall in serum Tg, implying a therapeutic effect. Attempts to identify such patients by increasing the dose of the diagnostic 131I tracer may lead to inhibition of subsequent uptake after the therapy dose, an effect referred to as 'stunning' and associated with a reduction in therapeutic effect. 123I is a short half-life gamma-emitter, thought to be unlikely to cause stunning, which may thus be more suitable than 131I for diagnostic imaging of thyroid cancer. DESIGN AND PATIENTS: The efficacy of the 123I radionuclide was determined in a longitudinal study of 12 patients who were selected only because they showed elevated serum Tg and a negative diagnostic 131I whole body study prior to therapy with 131I. RESULTS: There was almost complete concordance in uptake between 123I diagnostic imaging and the final scans carried out after 131I therapy (hereafter known as therapy studies) in 11 out of 12 patients at their first evaluation, in each of four patients receiving 123I at their second evaluation and in a single patient receiving 123I at a third evaluation. One patient had a positive 123I study but a negative 131I therapy study: following therapy Tg declined from 5.5 pg/l to undetectable levels, implying a therapeutic effect, and suggesting that the negative uptake was not the result of stunning. Two negative diagnostic 123I studies were followed by negative therapy studies, and thus there were no false negatives. 123I correctly identified disease in the nine patients with metastases in the lungs, mediastinum and bone at the first evaluation, in all four patients at the second evaluation and in the single patient at the third evaluation. At the end of the study, patients had received up to three 131I therapy doses, Tg had risen in four patients, fallen in eight and become undetectable in one patient. CONCLUSIONS: 123I is highly sensitive in diagnosing local recurrence and metastatic disease, and produces scintigraphic images which concord well with uptake following 131I therapy. It is proposed that 123I imaging, in combination with serum Tg measurements, should replace 131I tracer imaging as an indicator of the potential efficacy of 131I therapy. Stunning, with its detrimental effects on 131I therapy, may thus be avoided. The possibility of false negative images due to the stunning phenomenon must always be borne in mind if there is a discrepancy between positive 131I imaging studies and a surprisingly negative subsequent 131I therapy scan.

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