Cushing's disease, pseudo-Cushing states and the dexamethasone test: a historical and critical review.

The dexamethasone (DXM) test has been widely used for diagnosing Cushing's disease (CD). The purpose of this paper is to review its diagnostic merit based on calculation of data extracted from earlier publications. Studies presenting individual values for patients with CD and normal subjects were identified through PubMed searches and references in pertinent studies. Calculation of the retrieved data demonstrated huge variation in the relative suppressibility, negative suppression being common. Furthermore, in almost each study retrieved, the pre and post DXM values were closely correlated. Finally, the generally accepted view that DXM causes less suppression in Cushing's disease than in euadrenal controls appears unfounded. A central issue in the definition of so-called "pseudo-Cushing's states" is failure to suppress cortisol secretion with DXM. From analysis of the literature it appears quite possible that this does not reflect a specific endocrine deficit, but a physiological "stress" reaction. The above issues question the diagnostic value of the test, in particular in clinically and biochemically borderline cases.

Long-term ECMO treatment in Jehovah's Witness patient without transfusions.

A previously healthy 60-year-old male presented with fever, general pain and a C-reactive protein (CRP) of 160 mg/L. He was prescribed doxycycline. In the emergency room three days later, he was intubated and had a saturation of 70% on 100% oxygen. The chest X-ray showed bilateral lobar pneumonia. Streptococcus pneumonia was later verified. As a Jehovah's Witness, he had refused blood transfusions, but accepted albumin. Two days after admission, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was started and the patient was then transported on ECMO to Stockholm. After two days, echocardiography showed right cardiac failure and the patient had to be converted to veno-arterial ECMO (VV-A ECMO) by cannulation of the left femoral artery. The haemoglobin decreased from 10.0 to 6.0 g/dL. Iron, folic acid, and erythropoietin were administered to stimulate erythropoesis. Romiplostim, to stimulate the production of platelets, was also started immediately. Blood samples were reduced to a minimum. The ECMO circuit was changed twice, using saline for priming, and the blood in the old circuit was then given back to the patient. The haemoglobin concentration varied between 4.5 and 6.0 g/dL during the ECMO treatment and the platelets between 80 and 140 x10(9)/L. After 44 days on ECMO, the patient was weaned off ECMO with 50% oxygen and nitric oxide (NO) at 20ppm in the ventilator. Four days after decannulation, he was transferred to a nearby intensive care unit. Long-term ECMO treatment without transfusion of blood products is possible. Being a Jehovah's Witness should not automatically be a contraindication for ECMO.

Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults.

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15 years). Peak incidence rates were observed in age groups 5-9 and 40-44 years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children.

Structure of delay in carotid surgery--an observational study.

OBJECTIVES AND DESIGN: Undelayed investigation and surgical treatment of symptomatic carotid artery stenosis are recommended as per guidelines on stroke prevention. We evaluated patient referral pathways and delays from symptom to surgery in Helsinki University Central Hospital (HUCH) region. MATERIALS AND METHODS: One hundred consecutive symptomatic patients scheduled for carotid endarterectomy (CEA) between August 2007 and September 2008 were identified and the delay between ischaemic index symptom and CEA was analysed. RESULTS: The median time from the index symptom to surgery was 47 days (range: 3-688 days). The longest delay was surgery related with a median of 25 days (range: 2-202 days) from the consultation of the vascular surgeon to the operation. Only 11% of the patients were operated within the recommended 2 weeks' time. It was more likely that CEA was performed within 2 weeks if an emergent consultation to Meilahti Hospital neurologist on call did take place (odds ratio (OR) 12.6, 95% confidence interval (CI) 1.5-104, p = 0.019). CONCLUSION: Delays from symptom to surgery were generally too long and the in-hospital door-to-knife time (DKT) was long mostly due to waiting for the operation theatre. The investigation of all stroke, amaurosis fugax and transient ischaemic attack patients should be performed on an emergency basis and most optimally centralised to hospitals were carotid surgery is performed.

Pituitary-gonadal axis: historical notes.

Though it was appreciated at a very early time that removal of gonads had evident consequences, the anatomy and function of the gonads were essentially unknown in the Antiquity. It was not until around 1600 that men like Vesalius, de Graaf and Leeuwenhoek initiated rational studies on the structure and function of the gonads. The close relationship between gonads and hypothalamus/pituitary was recognized less than 100 years ago. The last pituitary hormone with gonadotroph effect was discovered a generation ago. This paper briefly describes some major points in the development of our knowledge of the pituitary-gonadal function. Considering the huge number of studies involved, this review reflects but a tiny fraction of the work laid down over millennia within this field.

Craniopharyngioma: historical notes.

For centuries tumors have been described which today with some confidence can be diagnosed as craniopharyngiomas. It was not until 1904 Erdheim described what he called 'hypophysial duct tumors', and which Cushing later gave the name craniopharyngioma. The first operation for this neoplasm took place in 1909. It soon became evident that the outcome of surgery was rather dismal with high mortality and morbidity rates-even after corticosteroid therapy became available around 1950. Radiotherapy was introduced and later refined as radiosurgery. This paper presents a short survey of the accumulation of knowledge of craniopharyngiomas.

Radiofrequency ablation in the liver close to the bile ducts: can intraductal cooling offer protection?

BACKGROUND: One complication of radiofrequency ablation (RFA) of the liver is biliary duct damage. Intraductal cooling (IDC) has been proposed as a means of protection. METHODS: In the first experiment, designed to evaluate the influence of IDC on the RFA procedure per se and on lesion formation, lesions were created in vivo in pig liver with and without IDC. The RFA needle was placed with a 1.5-cm safety margin from the bile ducts. In the second experiment, designed to evaluate the potential protective effects of IDC, lesions were created close to a bile duct with and without IDC. RESULTS: With the safety margin, the RFA parameters and lesion size were not negatively affected by IDC. Microscopic examination revealed that IDC had a protective effect in most of the lesions created close to a bile duct. CONCLUSIONS: The IDC procedure was feasible and had no negative effect on the RFA procedure or the lesions. However, the protective effect of IDC was not statistically significant (p = 0.12).

Problems in Interpretation of the short ACTH test: an update and historical notes.

ACTH stimulation test has been used for many years. Some important questions remain unsettled. These are reviewed and discussed in detail. Interpretation of a short ACTH test rests on the fact that a close correlation exists between the responses in plasma cortisol concentrations after administration of ACTH and during insulin induced hypoglycaemia which previously was the standard test. It is generally assumed that the plasma cortisol concentration after ACTH (and insulin) mirrors the response in major stress situations (surgery and critical disease). This notion rests on few observations. Furthermore, extensive changes in protein binding of cortisol occur swiftly during stress. This complicates comparison between cortisol responses to ACTH and to critical disease. Based on published studies it is discussed whether the outcome of an ACTH test is an appropriate indicator of the need for glucocorticosteroid replacement. This issue is of particular importance when deciding if permanent glucocorticosteroid substitution is necessary or not.

Remaining cancer cells within the fibrosis after neo-adjuvant treatment for locally advanced rectal cancer.

AIM: To analyse the incidence and distribution of remaining cancer cells within the fibrosis induced by preoperative chemo-radiotherapy (CRT) for locally advanced rectal cancer. METHODS: The histopathological specimens from 46 patients operated on with extensive surgery for locally advanced rectal cancer after CRT were examined. The extension of fibrosis in relation to the mesorectal fascia (MRF) and the distribution of cancer cells within the fibrosis was examined using routine haematoxylin-eosin staining. In addition, immunohistochemical staining with CK20 was done to examine if cancer cells were missed by routine pathological work up. RESULTS: All specimens showed CRT induced fibrosis. Two specimens showed complete response without viable cancer cells (ypT0). The fibrosis was limited inside the MRF in three cases, adherent to or involved the MRF in ten cases and in 33 cases the fibrosis was obvious outside as well as inside the fascia. Twenty-one cases showed fibrosis on the surgical resection margin, and in 9 of these cancer cells were found on the surgical margin (R1, R2-resection). 37 patients had R0 resections and among those 24 showed fibrosis beyond the MFR and 13 had scattered cancer cells in the fibrosis along or outside the MRF. CONCLUSIONS: The rate of remaining cancer cells within the fibrosis was high in patients with locally advanced rectal cancer treated with CRT. Frequently cancer cells were detected near the border of the fibrosis. A complete resection of the fibrosis is therefore recommended to achieve an R0 resection after neo-adjuvant treatment.

The spontaneous course of pituitary adenomas and occurrence of an empty sella in untreated acromegaly.

Twenty-three untreated patients with acromegaly for 6-46 yr who were followed for 2-13 yr were studied. High resolution computed tomographic scans in 11 patients revealed herniation of the subarachnoidal space into the pituitary fossa (empty sella) and an intrasellar cyst in 2. Suprasellar tumor extension developed during the follow-up period in only 1 patient. Eleven patients previously (in 10 patients more than 4 yr earlier) had been treated with bromocriptine; 6 of these patients at follow-up had a solid intrasellar adenoma. Six of the patients with an empty sella or intrasellar cyst had had symptoms suggesting pituitary apoplexy. The sellar volume did not increase during follow-up in any patient with an empty sella. Plasma GH levels (basal and mean concentrations during an oral glucose load) increased (greater than 50 ng/ml) in 3 and decreased in 3 patients during follow-up. Normalization of plasma GH levels was rare, and physical well-being with complete absence of acromegalic symptoms was reported by only 4 patients. These results demonstrate that GH-secreting pituitary tumors may remain stationary for extended periods of time and that complete or partial disappearance occurs frequently, probably as a result of pituitary adenoma infarction.

Urinary excretion of cortisol in acromegaly.

Free urinary cortisol excretion was measured in 19 patients with acromegaly and 19 matched controls with other pituitary disorders who were comparable with regard to age, sex, and adrenocortical response to ACTH. Excretion of cortisol was significantly higher (P less than 0.01) in the acromegalics (mean, 161 micrograms/24 h or 444 nmol/24 h) compared to the controls (mean, 82 micrograms/24 h or 226 nmol/24 h) normal subjects (mean, 85 micrograms/24 h or 235 nmol/24 h). Seven of the acromegalics had excretion of urinary cortisol exceeding the upper normal limit. The most probable cause is an increased glomerular filtration of cortisol.

Value of the 30-minute adrenocorticotropin (ACTH) test in demonstrating hypothalamic-pituitary-adrenocortical insufficiency after acute ACTH deprivation.

Adrenocortical responsiveness to corticotropin was reestablished by daily administration of 1 mg ACTH depot for 4 days in seven patients with secondary adrenocortical insufficiency. Peak plasma cortisol concentrations during a 30-min ACTH test performed 2 days after stopping injection of ACTH depot increased in all seven subjects (they were normal in five subjects) compared to the initial subnormal responses. Repeated short ACTH tests 5, 8, and 12 days after the last administration of ACTH depot showed a gradual decrease in plasma cortisol responses. When tested 8 days after the last ACTH depot injection was given all seven patients again had a subnormal response to ACTH. Thus, acute ACTH deprivation leads to an impaired adrenocortical response at a short ACTH test within 8-12 days.

Reliability of the 30-minute ACTH test in assessing hypothalamic-pituitary-adrenal function.

An insulin hypoglycemia test and a 30-min ACTH test were performed in 90 patients with proved or suspected hypothalamic-pituitary-adrenal hypofunction and in 10 normal subjects. The peak plasma cortisol concentration during hypoglycemia and the cortisol concentration at 30 min after injection of 250 micrograms corticotropin 1-24 were compared. A very close correlation (r = 0.92) was found between the the two concentrations, with no major discrepancy in any case. It is concluded that the short ACTH test accurately reflects the integrated hypothalamic-pituitary-adrenal function, as assessed by the insulin hypoglycemia test.

Plasma corticotropin and cortisol in patients with pituitary adenomas.

Plasma ACTH and cortisol were measured during insulin-induced hypoglycemia in 39 patients with a pituitary adenoma or after hypophysectomy and in 26 healthy persons. Adrenocortical insufficiency was defined as failure to increase plasma cortisol to at least 500 nmol/liter (18 microgram/dl) during hypoglycemia. No proper distinction was possible between patients with normal and impaired cortisol response to hypoglycemia on the basis of the ACTH results. When all 39 patients were compared to the 26 controls, the cortisol results differed significantly, but those of ACTH did not. These results demonstrate a limited value of ACTH measurements in secondary adrenocortical failure.

Bone disorder in men with chronic alcoholism: a reversible disease?

Disturbances in bone metabolism and histology have been recognized in chronic alcoholism. It has not been established whether they are reversible and the cause remains unclear. We studied various serum and urine variables (including serum PTH, calcium, D-vitamins, and osteocalcin concentrations), bone mineral content, and bone histomorphometrics in men who at present abused alcohol and compared the results to those from men who previously had abused alcohol but who had abstained from alcohol for at least 2 yr and from normal men. No significant differences were found in bone mineral content at the two measuring sites (distal forearm, lumbar spine) between drinkers, abstainers, and controls though a considerable proportion of both current drinkers and abstainers had subnormal values. Bone formation rate and turnover (expressed by the activation frequency) was significantly reduced in the current drinkers who also had lower serum PTH, 1,25-dihydroxycholecalciferol, and osteocalcin concentrations. Men who had abstained from alcohol consumption for at least 2 yr had results similar to those from normal men, suggesting that the disturbances in bone metabolism in men abusing alcohol are reversible. The decrease in bone turnover in the drinkers may be explained by the observed reduction in plasma PTH concentration or a direct toxic effect of ethanol on bone tissue leading to a deficient recruitment of osteogenic cells.

Incidence and late prognosis of cushing's syndrome: a population-based study.

The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 [95% confidence interval (CI), 2.34-5.33]. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained.

Pituitary apoplexy, the Houssay phenomenon, and accelerated proliferative retinopathy.

A 42-year-old man with diabetes mellitus and probably acromegaly had a pituitary apoplexy with left-sided oculomotor palsy. There was an immediate fall in blood glucose concentration. Pituitary insufficiency promptly developed. Blood glucose levels remained normal for the next two years. During the first year after the pituitary apoplexy, severe proliferative retinopathy developed in the left eye, which became almost blind. Only mild retinopathy was present on the right side. Plasma concentrations of growth hormone remained low after the apoplexy, and the acromegalic features subsided. The explanation of these findings may be that the proliferative retinal angiopathy was caused by compression of the cavernous sinus at the time of the apoplexy. This would lead to impaired venous drainage, thus resembling occlusion of the central retinal vein, which may cause retinopathy similar to that seen in diabetes mellitus.

Coronary risk factors and plasma sex hormones.

Recent studies have reported higher plasma estradiol levels in male survivors of acute myocardial infarction. This finding has raised the possibility that hyperestrogenemia may consitiute a separate coronary risk factor. In 443 men, aged 30, 40, 50, and 60, we assessed the relationship between plasma levels of estradiol, testosterone, and testosterone-binding globulin and coronary risk factors: fasting plasma concentrations of triglyceride, cholesterol, and high-density lipoprotein, blood pressure, and smoking and leisure-time physical activity patterns. Plasma estradiol concentrations were found to correlate significantly with body weight. After adjustment for this association, we found that the mean plasma estradiol concentration still was significantly higher in smokers than in nonsmokers. No other correlation could be estabilished between plasma hormone levels and coronary risk factors. The relative hyperestrogenemia reported in men with previous myocardial infarction may be due to an effect of smoking but may also reflect the relationship between body weight and plasma estradiol levels. Future studies should consider the demonstrated association between plasma estrogen levels and smoking.

Nuclear-DNA content and p53 immunostaining in oral squamous-cell carcinoma - an analysis of a consecutive 10-year material.

In a retrospective analysis of 91 consecutive oral carcinomas we reviewed all patient records and weighed clinicopathological parameters against the results of image DNA cytometry and p53 immunhistochemical staining of the initial diagnostic biopsies. Eighty-seven percent of the biopsies were either aneuploid or nondiploid and there was a significant correlation between poorly differentiated tumours and aneuploidy. Sixty-nine percent of the tumours were p53 positive. DNA aberration or p53 positivity had no significant impact on prediction of survival or susceptibility to radiotherapy. In a multivariate analysis, T category had the greatest predictive value concerning survival. There was no correlation between p53 positivity and smoking.

Stromelysin-3 mRNA expression in dysplasias and invasive epithelial cancer of the larynx.

Matrix metalloproteinases are believed to play an important role in tumor progression, invasion and metastasis. In order to investigate if the expression of stromelysin-3 (ST3) mRNA could add prognostic information concerning invasive laryngeal cancer and/or be indicative of a high risk for tumor progression in laryngeal dysplasias ST3 expression was analyzed by in situ hybridisation of formalin fixed paraffin embedded laryngeal specimens. Furthermore, all specimens underwent image cytometry (ICM) DNA analysis, and, p53 immunostaining. Invasive epithelial cancer, both localized (T1, T2) cancers, cured, as well as not cured, by radiotherapy, and cases with regional lymph node metastases were studied. Furthermore, high grade and low grade dysplasias, selected for rapid, slow and non-progression, as well as non-neoplastic inflammatory lesions were investigated. Expression of the ST3 gene was found in 9 out of 14 (64%) invasive cancer lesions, and in 3 out of 10 (30%) dysplasias, thus indicating that ST3 expression correlates to tumor progression. The ST3 positive laryngeal cancer lesions displayed a higher degree of DNA aberration than the ST3 negative lesions thus suggesting that ST3 positivity could indicate highly malignant tumors. Of the three ST3 positive dysplasias, the first progressed rapidly to cancer in situ with suspected microinvasion. The second ST3 positive dysplasia progressed to invasive cancer within five months. The third ST3 positive dysplasia had been radically excised and hereby cured. All but one of the dysplastic lesions showed p53 immunoreactivity, and all dysplasias exhibited aneuploid cells. ST3 expression appears to be a late event in the multistage process of carcinogenesis and could prove useful as an indicator of dysplasias with imminent risk for progression to invasive cancer.