Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms that originate from endocrine glands such as the pituitary, the parathyroids, and the (neuroendocrine) adrenal, as well as ...endocrine islets within glandular tissue (thyroid or pancreatic) and cells dispersed between exocrine cells, such as endocrine cells of the digestive (gastroenteropancreatic) and respiratory tracts. Conventionally, NETs may present with a wide variety of functional or nonfunctional endocrine syndromes and may be familial and have other associated tumors. Assessment of specific or general tumor markers offers high sensitivity in establishing the diagnosis and can also have prognostic significance. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogs and metaiodobenzylguanidine. Successful treatment of disseminated NETs requires a multimodal approach; radical tumor surgery may be curative but is rarely possible. Well-differentiated and slow-growing gastroenteropancreatic tumors should be treated with somatostatin analogs or α-interferon, with chemotherapy being reserved for poorly differentiated and progressive tumors. Therapy with radionuclides may be used for tumors exhibiting uptake to a diagnostic scan, either after surgery to eradicate microscopic residual disease or later if conventional treatment or biotherapy fails. Maintenance of the quality of life should be a priority, particularly because patients with disseminated disease may experience prolonged survival.
To investigate the early and late outcomes of patients with Cushing's disease (CD) submitted to a neurosurgical procedure as first-line treatment.
In this single-centre retrospective case notes ...study, 131 patients with CD with a minimum follow-up period of 6 years (124 operated by transsphenoidal surgery (TSS) and seven by the transcranial approach) were studied. Apparent immediate cure: post-operative 0900 h serum cortisol level <50 nmol/l; remission: cortisol insufficiency or restoration of 'normal' cortisol levels with resolution of clinical features; and recurrence: dexamethasone resistance and relapse of hypercortisolaemic features.
In patients operated by TSS, remission of hypercortisolaemia was found in 72.8% of 103 microadenomas and 42.9% of 21 macroadenomas, with recurrence rates 22.7 and 33.3% respectively with a 15-year mean follow-up (range, 6-29 years). Of 27 patients with microadenomas operated after 1991, with positive imaging and pathology, 93% obtained remission with 12% recurrence. In multivariate analysis, the time needed to achieve recovery of hypothalamo-pituitaryadrenal axis was the only significant predictor of recurrence; all patients who recurred showed recovery within 3 years from surgery: 31.3% of patients had total hypophysectomy with no recurrence; 42% of patients with selective adenomectomy and 26.5% with hemi-hypophysectomy showed recurrence rates of 31 and 13% respectively (χ(2)=6.275, P=0.03). Strict remission criteria were not superior in terms of the probability of recurrence compared with post-operative normocortisolaemia.
Lifelong follow-up for patients with CD appears essential, particularly for patients who have shown rapid recovery of their axis. The strict criteria previously used for 'apparent cure' do not appear to necessarily predict a lower recurrence rate.
Ergotism is the long-term ergot poisoning by ingestion of rye or other grains infected with the fungus
and more recently by excessive intake of ergot drugs. It has either neuropsychiatric or vascular ...manifestations. In the Middle Ages, the gangrenous poisoning was known as St. Anthony's fire, after the order of the Monks of St. Anthony who were particularly skilled at treating the condition. In 1917, Prof. Arthur Stoll returned home to Switzerland from Germany, to lead the development of a new pharmaceutical department at Sandoz Chemical Company. Stoll, using the special methods of extraction learned from his work with his mentor Willstetter, started his industrial research work with ergot. He succeeded in isolating, from the ergot of rye, ergotamine as an active principle of an old popular remedy for excessive post-partum bleeding. The success of this discovery occurred in 1918 and was translated into a pharmaceutical product in 1921 under the trade name Gynergen. In subsequent work, Stoll and his team were leaders in identifying the structure of the many other alkaloids and amines produced by
This was the cultural background and scientific foundation on which bromocriptine was discovered.
Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to ...1783, he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.
Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. ...Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone.
We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly.
The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups.
On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.
Cyclical Cushing's syndrome may render the diagnosis and management of Cushing's disease difficult. The aim of the present study was to investigate the prevalence of cyclicity and variability in ...patients with Cushing's disease, and to identify putative distinctive features.
Retrospective case-note study.
We analysed the case records of 201 patients with Cushing's disease in a retrospective case-note study. Cyclicity was considered as the presence of at least one cycle, defined as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The fluctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, defined the variability.
Thirty (14.9%; 26 females) patients had evidence of cyclicity/variability. 'Cycling' patients were older but no difference in sex or paediatric distribution was revealed between 'cycling' and 'non-cycling' patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identification was observed in 'cycling' compared with 'non-cycling' patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identification of the adenoma were associated with an increased risk of cyclic disease.
This large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushing's disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specific features can be used as markers.
Context: Cushing’s disease as a result of a pituitary macroadenoma is an uncommon cause of Cushing’s syndrome, and reports in the published literature are few and of limited size.
Objective: Our ...objective was to establish the clinical and biochemical characteristics of macroadenomas associated with Cushing’s disease compared with a large cohort of microadenomas and to assess their response to therapy.
Design: We conducted a retrospective case-records study for the years 1964–2001.
Setting: The study occurred at a tertiary referral hospital center.
Patients: Patients had Cushing’s disease presenting with a pituitary macroadenoma, in comparison with a large group of microadenoma patients.
Interventions: Interventions included therapy with surgery and radiotherapy.
Main Outcome Measures: Outcome measures included basal and dynamically responsive plasma ACTH and cortisol levels and response to treatment.
Results: We identified 18 patients with Cushing’s disease secondary to a macroadenoma; basal 0900 h plasma ACTH was 135.8 ± 32.5 and 45.0 ± 4.3 ng/liter (mean ± sem), respectively, in macroadenomas and microadenomas (P = 0.013). Mean 0900 h serum cortisol was significantly increased in the macroadenomas (27.5 ± 3.0 μg/dl, 759.6 ± 82.6 nmol/liter, vs. 22.6 ± 0.6 μg/dl, 624.7 ± 16.4 nmol/liter) (P = 0.021). Testing with high-dose dexamethasone showed less suppression in the macroadenomas (57.6 ± 8.7% vs. 74.4 ± 2.1%; P = 0.02) and an attenuated ACTH response to CRH. For all biochemical variables there was considerable overlap between the two groups. Few patients with macroadenomas were cured by surgery.
Conclusions: Pituitary macroadenomas causing Cushing’s disease have biochemical features largely distinct from patients harboring microadenomas but represent one end of a continuum.
Shiga toxin-producing Escherichia coli (STEC) O157:H7 and related non-O157 STEC strains are enteric pathogens of public health concern worldwide, causing life-threatening diseases. Cattle are ...considered the principal hosts and have been shown to be a source of infection for both foodborne and environmental outbreaks in humans. The aims of this study were to investigate risk factors associated with sporadic STEC infections in humans in New Zealand and to provide epidemiological information about the source and exposure pathways.
During a national prospective case-control study from July 2011 to July 2012, any confirmed case of STEC infection notified to regional public health units, together with a random selection of controls intended to be representative of the national demography, were interviewed for risk factor evaluation. Isolates from each case were genotyped using pulsed-field gel electrophoresis (PFGE) and Shiga toxin-encoding bacteriophage insertion (SBI) typing.
Questionnaire data from 113 eligible cases and 506 controls were analysed using multivariate logistic regression. Statistically significant animal and environmental risk factors for human STEC infections were identified, notably 'Cattle livestock present in meshblock' (the smallest geographical unit) (odds ratio 1.89, 95% CI 1.04-3.42), 'Contact with animal manure' (OR 2.09, 95% CI 1.12-3.90), and 'Contact with recreational waters' (OR 2.95, 95% CI 1.30-6.70). No food-associated risk factors were identified as sources of STEC infection. E. coli O157:H7 caused 100/113 (88.5%) of clinical STEC infections in this study, and 97/100 isolates were available for molecular analysis. PFGE profiles of isolates revealed three distinctive clusters of genotypes, and these were strongly correlated with SBI type. The variable 'Island of residence' (North or South Island of New Zealand) was significantly associated with PFGE genotype (p = 0.012).
Our findings implicate environmental and animal contact, but not food, as significant exposure pathways for sporadic STEC infections in humans in New Zealand. Risk factors associated with beef and dairy cattle suggest that ruminants are the most important sources of STEC infection. Notably, outbreaks of STEC infections are rare in New Zealand and this further suggests that food is not a significant exposure pathway.
Cushing’s syndrome requires a screening test of high sensitivity, followed by biochemical evaluation of the source of the tumor when the cause is ACTH dependent. The high-dose dexamethasone ...suppression test is still in common use as an aid in differential diagnosis, although its value has been queried. We have routinely used the low-dose dexamethasone suppression test for many years in the diagnosis of Cushing’s syndrome but noticed that patients with pituitary-dependent Cushing’s syndrome or Cushing’s disease, usually showed some degree of suppression of their serum cortisol, compared to those with the ectopic ACTH syndrome. We therefore analyzed retrospectively the serum cortisol responses during the low-dose dexamethasone suppression test and the high-dose dexamethasone suppression test in 245 patients with ACTH-dependent Cushing’s syndrome and compared the diagnostic utility of each test either alone or in combination with a standard test using CRH. Evaluation of the serum cortisol response at 24 and 48 h during the low-dose dexamethasone suppression test correctly identified 98% of patients with ACTH-dependent Cushing’s syndrome and distinguished between pituitary and ectopic causes with a sensitivity of 82% and a specificity of 79%. In the same patients, the serum cortisol response to the high-dose dexamethasone suppression test had a slightly higher sensitivity (91%) and specificity (80%). However, the combined criteria of a more than 30% suppression of serum cortisol during the low-dose dexamethasone suppression test and/or a more than 20% increase in the CRH test had a significantly higher sensitivity (97%) and specificity (94%) than either the high-dose dexamethasone or the CRH tests alone in the differential diagnosis of ACTH-dependent Cushing’s syndrome. It produced equivalent information to that when high-dose and CRH test results were combined. We therefore conclude that in our patient series, the serum cortisol response during the low-dose dexamethasone suppression test is highly sensitive in diagnosing Cushing’s syndrome and, combined with the results of the serum cortisol response to the CRH test, offered a safe and cost-effective test in the differential diagnosis of ACTH-dependent Cushing’s syndrome. There does not appear to be any necessity for retaining the high-dose dexamethasone suppression test in this diagnostic work-up.
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.
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.
Mean serum IGF-1 concentrations fell by at least 50%: 467 μg/L (SE 24), 526 μg/L (29), and 523 μg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0·001), whereas growth hormone increased by 12·5 μg/L (2·1), 12·5 μg/L (3·0), and 14·2 μg/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 μg/L (2·5) at baseline, rose to 15·2 μg/L (2·4) on drug, and fell back within 30 days of withdrawal to 8·3 μg/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).
Pegvisomant is an effective medical treatment for acromegaly.
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