Fractionated stereotactic radiotherapy in patients with acromegaly: an interim single-centre audit.

AIM: To evaluate the effect of fractionated stereotactic radiotherapy (FSRT) in acromegaly in a retrospective analysis. PATIENTS AND METHODS: Thirty-four patients (17 females, median 43 years (range 30-74)) with acromegaly were treated with FSRT (conformal dynamic arcing, dose 54 Gy, 27-30 fractions) between January 1998 and April 2007. Of the 34 patients, 32 had undergone transsphenoidal adenotomy, and 28 were on medical therapy before FSRT. Patients on medical therapy continued this during and after the irradiation. The treatment was gradually decreased/withdrawn after careful assessment. RESULTS: Magnetic resonance scanning of the pituitary gland 34 months (median, range 11-95) after irradiation showed stable or reduced volume of the remaining tumour tissue in 31 of 34 patients (91%). Seventeen patients (50%) were biochemically controlled (normalised nadir GH during oral glucose tolerance test and IGF1 <+2 S.D.) 30 months after FSRT (median, range 6-60), and ten of them had true biochemical remission (off medical therapy) 30 months after FSRT (median, range 12-69). Of 28 patients with one or more functioning pituitary axes before irradiation, 8 (29%) developed further deficit of one or two pituitary axes 48 months (median, range 6-102) after FSRT. Of 34 patients, 20 still required medical treatment for acromegaly at the end of this study, mainly those with a short follow-up period after irradiation. CONCLUSION: The FSRT seems promising in terms of treatment of acromegaly. Longer follow-up is, however, needed to assess the overall efficacy and safety of FSRT for acromegaly.

Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective single-centre study.

OBJECTIVE: To assess the prevalence of hypopituitarism following traumatic brain injury (TBI), describe the time-course and assess the association with trauma-related parameters and early post-traumatic hormone alterations. DESIGN: A 12-month prospective study. PATIENTS: Forty-six consecutive patients with TBI (mild: N = 22; moderate: N = 9; severe: N = 15). MEASUREMENTS: Baseline and stimulated hormone concentrations were assessed in the early phase (0-12 days post-traumatically), and at 3, 6 and 12 months postinjury. Pituitary tests included the Synacthen-test (acute +6 months) and the insulin tolerance test (ITT) or the GHRH + arginine test if the ITT was contraindicated (3 + 12 months). Insufficiencies were confirmed by retesting. RESULTS: Early post-traumatic hormone alterations mimicking central hypogonadism or hypothyroidism were present in 35 of the 46 (76%) patients. Three months post-traumatically, 6 of the 46 patients failed anterior pituitary testing. At 12 months, one patient had recovered, whereas none developed new insufficiencies. All insufficient patients had GH deficiency (5 out of 46), followed by ACTH- (3 out of 46), TSH- (1 out of 46), LH/FSH- (1 out of 46) and ADH deficiency (1 out of 46). Hypopituitary patients had more frequently been exposed to severe TBI (4 out of 15) than to mild or moderate TBI (1 out of 31) (P = 0.02). Early endocrine alterations including lowered thyroid and gonadal hormones, and increased total cortisol, free cortisol and copeptin were positively associated to TBI severity (P < 0.05), but not to long-term development of hypopituitarism (P > 0.1), although it was indicative in some. CONCLUSION: Long-term hypopituitarism was frequent only in severe TBI. During the 3-12 months follow-up, recovery but no new insufficiencies were recorded, indicating manifest hypothalamic or pituitary damage already a few months postinjury. Very early hormone alterations were not associated to long-term post-traumatic hypopituitarism. Clinicians should, nonetheless, be aware of potential ACTH deficiency in the early post-traumatic period.

Prevalence and predictive factors of post-traumatic hypopituitarism.

OBJECTIVE: To estimate the prevalence and predictive factors of hypopituitarism following traumatic brain injury (TBI). DESIGN: A cross-sectional cohort study. PATIENTS: One hundred and four hospitalized TBI patients (26F/78M), median age 41 (range 18-64) years, body mass index (BMI) 25 (17-39) kg/m(2); severity: mild [Glasgow Coma Scale (GCS) score 13-15) n = 44, moderate (GCS 9-12) n = 20, severe (GCS < 9) n = 40]. MEASUREMENTS: Patients were evaluated 13 (10-27) months post-injury, with measurement of baseline (0800-1000 h) and post-stimulatory hormonal levels during an insulin tolerance test (ITT) (86%) or, if contraindicated, an arginine(arg)-GHRH test + Synacthen test (14%). Insufficiencies were confirmed by retesting. RESULTS: Hypopituitarism was found in 16 (15%) patients, affecting one axis in 10, two axes in four and more than two axes in two patients. The GH axis was most frequently affected (15%), followed by secondary hypoadrenalism (5%), hypogonadism (2%), hypothyroidism (2%) and diabetes insipidus (2%). The risk of pituitary insufficiency was increased in patients with severe TBI as opposed to mild TBI [odds ratio (OR) 10.1, 95% confidence interval (CI) 2.1-48.4, P = 0.004], and in those patients with increased intracerebral pressure [OR 6.5, 95% CI 1.0-42.2, P = 0.03]. Patients with only one affected axis were all GH deficient; 60% (n = 6) of these were overweight or obese. CONCLUSION: The prevalence of hypopituitarism was estimated at 16%. Although high, this value was lower than previously reported, and may still be overestimated because of well-known confounding factors, such as obesity. Indicators of increased TBI severity were predictive of hypopituitarism, with a high negative predictive value. Neuroendocrine evaluation should therefore be considered in patients with severe TBI, and in particular in those with increased intracerebral pressure (ICP).

A prospective PET study of patients with glioblastoma multiforme.

OBJECTIVE: To study the post-surgical metabolic and structural cerebral changes in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: We examined ten patients prospectively with newly diagnosed GBM. All patients were primarily treated with surgery, followed by chemotherapy (carmustine, cisplatine and etoposide) and radiotherapy. Positron emission tomography (PET) was used to measure tumor- and cerebral metabolism. CT or MRI was used to estimate tumor volume by measurements of tumor area. RESULTS: Tumor metabolism was not increased during chemotherapy (P = 0.71), but increased during radiotherapy (P = 0.01). CT/MRI showed similar results with no increase in tumor area during chemotherapy (P = 0.33) but increase during radiotherapy (P = 0.002). During the entire study, tumor metabolism and area increased evenly (P = 0.01). CONCLUSIONS: Our study did not show a gain of PET compared with structural imaging in the prospective evaluation of GBM. We found a difference in metabolic increase and tumor growth between the two treatment regimens, although this finding has limited relevance due to the design of the study.

Adrenocortical insufficiency after pituitary surgery: an audit of the reliability of the conventional short synacthen test.

BACKGROUND: Assessment of the hypothalamic-pituitary-adrenal (HPA) axis after pituitary surgery is important for appropriate decision making regarding replacement therapy. The synacthen test is often used but is questioned, as time has to elapse for adrenal atrophy to develop. OBJECTIVE: To audit the use of the 250 microg synacthen test after transsphenoidal adenomectomy. METHODS: A retrospective study of 110 patients submitted to first-time transsphenoidal adenomectomy. Anterior pituitary testing was performed preoperatively, 1 week and 1, 3, 6 and 12 months postoperatively. The adrenocortical function was tested by a synacthen test (250 microg synacthen i.v.). RESULTS: Thirty-two out of 71 patients with normal HPA function before surgery developed insufficiency postoperatively, seven patients presenting an insufficient test response after 1 week, 16 after 1 month and nine after 3 months, whereas none became insufficient during the remaining follow-up. Three patients presented symptomatic adrenal insufficiency during the first postoperative week despite a normal test. All of these developed an insufficient test 1 month postoperatively. A 1-week basal plasma cortisol > 400 nmol/l indicated HPA sufficiency, whereas a basal cortisol < or = 100 nmol/l indicated insufficiency when related to the diagnosis based on the 3-month synacthen test. CONCLUSION: This study confirms that the synacthen test is of limited use in the early postoperative phase, because out of 62 patients with normal 1-week postoperative synacthen responses, 23 patients developed a test that was indicative of adrenal insufficiency over 1-3 months. Our results indicate that a large proportion of patients should be considered for hydrocortisone replacement therapy up to 3 months postoperatively followed by reassessment of the HPA axis.

Cellular telephones and risk for brain tumors: a population-based, incident case-control study.

OBJECTIVE: To evaluate a possible association of glioma or meningioma with use of cellular telephones, using a nationwide population-based case-control study of incident cases of meningioma and glioma. METHODS: The authors ascertained all incident cases of glioma and meningioma diagnosed in Denmark between September 1, 2000, and August 31, 2002. They enrolled 252 persons with glioma and 175 persons with meningioma aged 20 to 69. The authors also enrolled 822 randomly sampled, population-based controls matched for age and sex. Information was obtained from personal interviews, medical records containing diagnoses, and the results of radiologic examinations. For a small number of cases and controls, the authors obtained the numbers of incoming and outgoing calls. They evaluated the memory of the respondents with the Mini-Mental State Examination and obtained data on socioeconomic factors from Statistics Denmark. RESULTS: There were no material socioeconomic differences between cases and controls or participants and non-participants. Use of cellular telephone was associated with a low risk for high-grade glioma (OR, 0.58; 95% CI, 0.37 to 0.90). The risk estimates were closer to unity for low-grade glioma (1.08; 0.58 to 2.00) and meningioma (1.00; 0.54 to 1.28). CONCLUSION: The results do not support an association between use of cellular telephones and risk for glioma or meningioma.

Detection of unknown primary tumours in patients with cerebral metastases using whole-body 18F-flouorodeoxyglucose positron emission tomography.

Identification of the unknown primary tumours in patients presenting with cerebral metastasis is a continued diagnostic challenge. Despite extensive and lengthy diagnostic work-up, the primary tumours will remain obscure in a significant proportion of the patients. The aim of this study was to evaluate the use of whole-body 18-F-fluorodeoxyglucose positron emission tomography (18FDG PET) scanning in this pursuit. Sixteen patients aged 34-74 years, with histologically confirmed metastatic brain tumours, were included in the study. Whole-body 18FDG PET identified pulmonary foci of probable primary tumours in all patients. Subsequent confirmation of tumour tissue was determined either by direct histological verification or indirectly by the observation of lesion appearance or lesion growth on structural imaging. This could only be obtained in eight of 16 patients, all defined as true positive. Of the remaining eight, a biopsy could not be sampled from seven patients, because of death or limited follow-up investigations, and one patient had pulmonary malignant melanoma metastases. Whole-body 18FDG PET scanning is a sensitive tool in the search for unknown primary tumours of patients with confirmed cerebral metastases allowing early and focused histological confirmation from suspicious lesions.

[Endoscopic closure of cranionasal cerebrospinal fluid fistulas with the use of neuronavigation--"Computer Aided Surgery"]. / Endoskopisk lukning af kranionasale liquorfistler med anvendelse af neuronavigation--"Computer Aided Surgery".

INTRODUCTION: Conventionally, cranionasal cerebrospinal fluid (CSF) fistulas have been closed by repair of the dural defect via an open craniotomy. These techniques may be cumbersome, not without complications, and far from successful. In recent years, endoscopic techniques have been developed in the field of nasal surgery and neurosurgery. Furthermore, by means of computer-aided surgery or neuronavigation, it is possible to identify the surgical track with a high degree of accuracy and, by the same token, identify the defect in the cranium. METHOD: By combining the endoscopic technique with computer-aided surgery, we have operated on six patients with cranionasal CSF fistulas endonasally. The fistula was confirmed before surgery by subaracnoidal injection of fluorescein. RESULTS: The surgery was successful and without any complications in all six cases. DISCUSSION: The method is recommended as the operation of first choice for cranionasal CFS fistulas, as compared to transcranial surgery. It is probably more efficient and with fewer complications than conventional surgery. A collaboration between neurosurgeons and ENT surgeons, like ours, can be recommended.

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.

Treatment of newly diagnosed glioblastoma multiforme with carmustine, cisplatin and etoposide followed by radiotherapy. A phase II study.

A meta-analysis and several studies of patients with grade III and IV gliomas have indicated that the addition of nitrosurea based chemotherapy to surgery and radiation may improve survival. We performed a phase II study of pre-irradiative chemotherapy with BCNU, cisplatin and etoposide. This implies a short total treatment duration and a reliable response evaluation. The treatment schedule was three cycles of BCNU 200 mg/m2 i.v. on day 1, cisplatin 20 mg/m2 i.v. on day 1-5 and etoposide (VP-16) 100 mg/m2 i.v. on day 1-5, given every five weeks and followed by localized radiation, 60 Gy in 30 fractions. Twenty-nine patients with newly diagnosed glioblastoma multiforme (GBM), mean age 50 (27-66) and performance status (PS) 0-2 were included. Using the Macdonald criteria 33% had partial remission (PR), 41% stable disease (SD) and 26% progressive disease (PD) after chemotherapy. After additional radiation 44% had PR, 37% SD and 19% PD. Non-hematological toxicity and leukopenia was mild, but thrombocytopenia (TP) frequent. Grade III and IV TP occurred in 25% and 57% respectively, and grade III bleeding in 45%. No severe or fatal complications was seen. Median time to progression (TTP) was 7.6 months (6.0-9.1) and median survival was 11.4 months (10.1-12.7). We conclude that this regimen is effective and feasible in patients with GBM. The short course pre-irradiatory chemotherapy may be less cumbersome than adjuvant chemotherapy and the regimen may be even more active in grade III gliomas.

[Do Danish surgeons have problems of conscience and responsibility? Results of a preliminary questionnaire survey]. / Har danske kirurger samvittighedsproblemer og ansvarsfølelse? Resultater af en proeliminoer spørgeskemaundersøgelse.

A survey among Danish surgeons was conducted in order to elucidate whether Danish surgeons have problems of conscience related to their operative activity, especially when the results of the latter are unsatisfactory or lead to the death of the patient. Forty-three surgeons returned a questionnaire. All surgeons agreed that the problem that was raised was a significant one. The majority of the surgeons were aware of a patient, whom they had operated on and where the result of surgery was unsatisfactory or even caused the death of the patient. These problems are only to a limited extent discussed at work, whereas they are more frequently dealt with at home.

[Craniopharyngiomas. Neurosurgical treatment and therapeutic results]. / Kraniofaryngeomer. Neurokirurgisk behandling og behandlingsresultater.

From 1984 to 1993, 24 patients were operated for craniopharyngeoma at the University Clinic of Neurosurgery, Rigshospitalet, Copenhagen. We undertook a retrospective study based on the patients' records in order to elucidate the course of the illness from the time of diagnosis until the end of treatment. The median age of the patients was 35 years (range 1.5-75 years). The follow-up period was one month-9.5 years. Preoperatively most patients had symptoms or clinical signs of compression of the optic pathways. Eighteen patients were operated by the transcranial route and six patients by the transsphenoidal route. Radical excision was achieved in 10 cases. Nine patients had recurrence of tumor. Postoperative endocrine disturbances were diagnosed in 19 cases. By the end of the follow-up eight patients were dead, of whom seven had had relapse of tumor. We recommend radical excision at the primary operation whenever possible, but the issue is controversial.