Dexamethasone-related adrenal insufficiency in patients with brain and skull base tumours.

PURPOSE: This study aimed to evaluate the prevalence of glucocorticoid-induced adrenal insufficiency in a cohort of patients with brain and skull base tumours and to identify factors which may predict its occurrence. METHODS: Patients with brain or skull base tumours attending for a short synacthen test (SST) (adrenocorticotropin hormone (ACTH) stimulation test) at a single institution over a 3-year period were retrospectively identified. Baseline demographics and dexamethasone exposure were examined. Only patients with dexamethasone exposure were included in the final analysis looking at the primary end point of SST failure. Fisher's exact test, Student's t test, Mann-Whitney test and the Kendall's tau-b test were used to evaluate the influence of age, gender, diagnosis and mean pituitary radiation dose on the primary endpoint. Receiver operating characteristic (ROC) curves were generated to explore the impact of duration and total exposure to dexamethasone on likelihood of SST failure. RESULTS: Thirty-one of 51 patients with previous dexamethasone exposure failed their first SST (61%). No significant relationship was demonstrated between age, gender, diagnosis or mean pituitary radiation dose and SST failure. Duration of and total exposure to dexamethasone were significantly associated with SST failure (p = 0.001 and p = 0.007, respectively). ROC curves generated values of 78 days and 171 mg days to give a sensitivity of 94 and 97%, respectively, to detect SST failure. CONCLUSIONS: Duration of dexamethasone use and total exposure predict for adrenal insufficiency in patients with brain and skull base tumours. Values derived from this study may be useful to identify patients at higher risk of adrenal suppression who require empirical hydrocortisone pending formal testing of the hypothalamic-pituitary-adrenal axis.

Evaluation of Response to Stereotactic Radiosurgery in Brain Metastases Using Multiparametric Magnetic Resonance Imaging and a Review of the Literature.

AIMS: Following stereotactic radiosurgery (SRS), brain metastases initially increase in size in up to a third of cases, suggesting treatment failure. Current imaging using structural magnetic resonance imaging (MRI) cannot differentiate between tumour recurrence and SRS-induced changes, creating difficulties with patient management. Combining multiparametric MRI techniques, which assess tissue physiological and metabolic information, has shown promise in answering this clinical question. MATERIALS AND METHODS: Multiparametric MRI techniques, including spectroscopy, diffusion and perfusion imaging, were used for the differentiation of radiation-related changes and tumour recurrence after SRS for intracranial metastases in six cases. All patients presented with enlargement of the treated lesion, an increase in perilesional brain oedema and aggravation or appearance of neurological signs and symptoms from 7 to 29 weeks after primary treatment. RESULTS: Multiparametric imaging helped to differentiate features of tumour progression (n = 4) from radiation-related changes (n = 2). A low apparent diffusion coefficient (ADC) <1000 × 10-6 mm2/s, high relative cerebral blood volume (rCBV) ratio > 2.1, high choline:creatine (Cho:Cr) ratio > 1.8 suggested tumour recurrence. A high ADC > 1000 × 10-6 mm2/s, low rCBV ratio < 2.1, Cho:Cr ratio < 1.8 suggested SRS-induced radiation changes. Multiparametric MRI diagnosis was confirmed by histology or radiological and clinical follow-up. CONCLUSION: Multiparametric MRI was helpful in the early identification of radiation-related changes and tumour recurrence and may be useful for monitoring treatment changes in intracranial neoplasms after SRS treatment.

Linear accelerator radiosurgery for arteriovenous malformations: Updated literature review.

Arteriovenous malformations (AVMs) are the leading causing of intra-cerebral haemorrhage. Stereotactic radiosurgery (SRS) is an established treatment for arteriovenous malformations (AVM) and commonly delivered using Gamma Knife within dedicated radiosurgery units. Linear accelerator (LINAC) SRS is increasingly available however debate remains over whether it offers an equivalent outcome. The aim of this project is to evaluate the outcomes using LINAC SRS for AVMs used within a UK neurosciences unit and review the literature to aid decision making across various SRS platforms. Results have shown comparability across platforms and strongly supports that an adapted LINAC based SRS facility within a dynamic regional neuro-oncology department delivers similar outcomes (in terms of obliteration and toxicity) to any other dedicated radio-surgical platform. Locally available facilities can facilitate discussion between options however throughput will inevitably be lower than centrally based dedicated national radiosurgery units.

Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors.

PURPOSE: To measure the oxygen status of human malignant brain tumors in vivo and to determine the activities and expression of bioreductive enzymes in these same human brain tumor samples, as a means of assessing their suitability as targets for bioreductive drug therapy. METHODS AND MATERIALS: A polarographic oxygen electrode was used to measure the intratumoral oxygen tension in twenty patients with malignant brain tumors during open brain surgery, performed under standard anaesthetic conditions. Six different tracks, each with a path length of 22 mm, were recorded per patient representing 192 readings. Following pO2 measurements the tumors were resected and stored in liquid N2 for subsequent bioreductive enzyme analysis. Eight human malignant brain tumors were assessed, by enzyme activity and western blot expression, for the presence of various bioreductive enzymes. These enzymes included DT-diaphorase, NADH cytochrome b5 reductase, and NADPH cytochrome P-450 reductase. Of these eight gliomas analyzed six samples were incubated with the bioreductive drug tirapazamine, in the presence of cofactor(s), to establish whether human brain tumors could metabolize this compound. RESULTS: Both the high grade intrinsic and metastatic brain tumors showed significant regions of hypoxia. All the tumors subjected to enzyme profiling contained the bioreductive enzymes, DT-diaphorase, NADH cytochrome b5 reductase and NADPH cytochrome P-450 reductase. Also all six of the brain tumors investigated could metabolize tirapazamine to the two-electron reduction product. CONCLUSION: These findings would favor primary brain tumors as suitable targets for bioreductive therapy.

Measurement of serum arabinitol by gas-liquid chromatography: limitations for detection of systemic candida infections.

The measurement of serum arabinitol in the diagnosis of systemic candidosis was evaluated using a gas-liquid chromatography technique in a cohort of at risk patients. The prevalence of seropositivity was low and did not correlate with evidence of infection. This technique is unlikely to achieve acceptance because it does not discriminate between patients with and without infection; it requires specialised equipment and it is expensive.

Development of sheep preimplantation embryos in media supplemented with glucose and acetate.

Two experiments were conducted to examine the effect of supplemental glucose (G; 1.5 mM) and/or acetate (A; 0.5 mM) on the development of early sheep embryos to blastocysts when cultured in vitro in glucose-free synthetic oviductal fluid (SOF)+sheep serum or bovine serum albumin (BSA). In Experiment 1, 2- to 4-cell, 8- to 16-cell and >16-cell embryos were cultured in SOF, SOF+G, SOF+A or SOF+G+A. All media were supplemented with 10% sheep serum. In addition, embryos were cultured in either microdrops under polysiloxane oil or in multiwell dishes. Overall, development to the blastocyst stage was 3%, 30% and 68% for 2- to 4-cell, 8- to 16-cell and >16-cell stages, respectively, suggesting that an 8-cell developmental block existed under our culture conditions. Glucose supplementation had little effect on embryo development, and no overall effect was observed from the addition of acetate. In Experiment 2, 8- to 16-cell embryos were cultured in SOF or SOF+G, both supplemented with BSA. Development to the blastocyst stage was 25% and 18%, respectively. The results show that the presence of glucose or acetate did little to enhance embryonic development in our incubation systems. Further work is required to evaluate fully the energy requirements for development of the early sheep embryo.

CBIT--context-based image transmission.

Few networks offer sufficient bandwidth for the transmission of high resolution two- and three-dimensional medical image sets without incurring significant latency. Traditional compression methods achieve bit-rate reduction based on pixel statistics and ignore visual cues that are important in identifying visually informative regions. This paper describes an approach to managing image transmission in which spatial regions are selected and prioritized for transmission so that visually informative data is received in a timely manner. This context-based image transmission (CBIT) scheme is a lossless form of progressive image transmission (PIT) in which gross structure, represented by an approximate iconic image, is transmitted first. Each part of this iconic image is progressively updated, using a simple set of rules that take into account viewing requirements. CBIT is realized using knowledge about image composition to segment, label, prioritize, and fit geometric models to regions of an image. Tests, using neurological images, show that, with CBIT, a valuable transmitted image is received with a latency that is about one-tenth that of traditional PIT schemes. Frequently, the necessary regions of the image are transmitted in about half the time taken to transmit the full image.

Rhinocerebral mucormycosis.

Rhinocerebral mucormycosis is a fungal diseases that has a 50% mortality. Its occurrence has increased, possibly because of greater use of chemotherapeutic agents that mya compromise the immunologic defenses of the host or alter the normal flora. The earliest signs, ulceration and pain, may appear in the mouth. In the patient described in this report, the autopsy showed that mucormycosis had entered the brain cells.

Audit of headache following resection of acoustic neuroma using three different techniques of suboccipital approach.

A retrospective case notes review using pain visual analogue scale (VAS) and assessment of analgesia required by patients in the post-operative period at 1, 3, 6, 12 and over 12 months following acoustic neuroma resection was performed. Glasgow Benefit Inventory (GBI) score was used to assess the change of quality of life and its relationship to pain following surgery. Questionnaires of 71 patients were included in the study, 23 of whom underwent wide craniotomy including dissection of upper cervical musculature (CE), 25 wide craniotomy with replacement of bone flap (CO) and 23 minimally invasive, approximately 2 x 2 cm, minicraniectomy (MCE). The minicraniectomy resulted in significantly diminished pain from third month post surgery as compared with wide craniectomy (p < 0.05) and patients required less analgesia. Similarly, CO patients have experienced significantly less pain than CE patients (p < 0.05), but only after 12 months following surgery. Although consistently less in absolute visual analogue scores, there was no statistically significant difference between the amount of pain recorded by CO and MCE patients. There was no correlation between gender or age and the VAS pain score. The mean Glasgow Benefit Inventory score for all patients was -6.6, and there was no significant difference between operation types, genders or age. Although bone flap replacement appears to diminish the amount of post-operative pain, minimal invasive technique resulted in least pain following acoustic neuroma resection in our patients.

Linear accelerator stereotactic radiosurgery for vestibular schwannomas: a UK series.

AIMS: To evaluate non-auditory toxicity and local control after linear accelerator stereotactic radiosurgery (SRS) for the treatment of vestibular schwannomas. MATERIALS AND METHODS: The institutional policy was to use SRS for radiologically progressing vestibular schwannomas. Case notes and plans were retrospectively reviewed for all patients undergoing SRS for vestibular schwannomas between September 2002 and June 2012. All patients were surgically immobilised using a BrainLab stereotactic head frame. The treatment plan was generated using BrainLab software (BrainScan 5.03). The aim was to deliver 12 Gy to the surface of the target with no margin. Patients with a minimum of 12 months of follow-up were included for toxicity and local control assessment. Radiological progression was defined as growth on imaging beyond 2 years of follow-up. Overall local control was defined in line with other series as absence of surgical salvage. RESULTS: Ninety-nine patients were identified. Two patients were lost to follow-up. After a median follow-up interval of 2.4 years, the actuarial radiological progression-free survival at 3 years was 100% and overall local control was also 100%. However, two patients progressed radiologically at 3.3 and 4.5 years, respectively. Twenty-one of 97 (22%) evaluable patients suffered trigeminal toxicity and this was persistent in 8/97 (8%). Two of 97 (2%) suffered long-term facial nerve toxicity (one with associated radiological progression causing hemi-facial spasm alone). One of 97 (1%) required intervention for obstructive hydrocephalus. No statistically significant dosimetric relationship could be shown to cause trigeminal or facial nerve toxicity. However, 7/8 patients with persistent trigeminal nerve toxicity had tumours in contact with the trigeminal nerve. CONCLUSIONS: SRS delivering 12 Gy using a linear accelerator leads to high local control rates, but only prospective evaluation will fully establish short-term toxicity. In this study, persistent trigeminal toxicity occurred almost exclusively in patients whose tumour was in contact with the trigeminal nerve.

Patterns of relapse in glioblastoma multiforme following concomitant chemoradiotherapy with temozolomide.

OBJECTIVE: Different methods for contouring target volumes are currently in use in the UK when irradiating glioblastomas post operatively. Both one- and two-phase techniques are offered at different centres. 90% of relapses are recognised to occur locally when using radiotherapy alone. The objective of this evaluation was to determine the pattern of relapse following concomitant radiotherapy with temozolomide (RT-TMZ). METHODS: A retrospective analysis of patients receiving RT-TMZ between 2006 and 2010 was performed. Outcome data including survival were calculated from the start of radiotherapy. Analysis of available serial cross-sectional imaging was performed from diagnosis to first relapse. The site of first relapse was defined by the relationship to primary disease. Central relapse was defined as progression of the primary enhancing mass or the appearance of a new enhancing nodule within 2 cm. RESULTS: 105 patients were identified as receiving RT-TMZ. 34 patients were not eligible for relapse analysis owing to either lack of progression or unsuitable imaging. Patterns of first relapse were as follows: 55 (77%) patients relapsed centrally within 2 cm of the original gadolinium-enhanced mass on MRI, 13 (18%) patients relapsed >4 cm from the original enhancement and 3 (4%) relapsed within the contralateral hemisphere. CONCLUSION: Central relapse remains the predominant pattern of failure following RT-TMZ. Single-phase conformal radiotherapy using a 2-cm margin from the original contrast-enhanced mass is appropriate for the majority of these patients. ADVANCES IN KNOWLEDGE: Central relapse remains the predominant pattern of failure following chemoradiotherapy for glioblastomas.

A cancer research UK pharmacokinetic study of BPA-mannitol in patients with high grade glioma to optimise uptake parameters for clinical trials of BNCT.

This paper describes results to-date from a human pharmacokinetic study which began recruitment in December 2007. Results are presented for a single patient recruited in December 2007. A second patient was recruited in July 2008 but detailed data are not available at the time of writing. The trial is an open-label, non-comparative, non-therapeutic study of BPA-mannitol in patients with high-grade glioma, who will be undergoing stereotactic brain biopsy as part of the diagnostic process before definitive treatment. The study investigates the route of infusion (intra-venous (IV) or intra-carotid artery) and in each case will assess the effect of administration of mannitol as a blood-brain barrier disrupter. All cohorts will receive a 2 h infusion of BPA-mannitol, and for some cohorts an additional mannitol bolus will be administered at the beginning of this infusion. Measurements are made by inductively coupled plasma mass spectrometry (ICP-MS) of (10)B concentration in samples of blood, urine, extra-cellular fluid in normal brain (via a dialysis probe), brain tissue around tumour and tumour tissue. Additional analysis of the tumour tissue is performed using secondary ion mass spectrometry (SIMS). The first patient was part of the cohort having intra-venous infusion without mannitol bolus. No serious clinical problems were experienced and the assay results can be compared with available patient data from other BNCT centres. In particular we note that the peak (10)B concentration in blood was 28.1 mg/ml for a total BPA administration of 350 mg/kg which is very consistent with the previous experience with BPA-fructose reported by the Helsinki group.

Intradural, extramedullary spinal cord compression from tuberculous granuloma.

A 19-year-old girl presented with acute cord compression following treatment for tuberculous meningitis. Magnetic resonance imaging showed a posterior compressive lesion between T1 and T4. At laminectomy, an intradural extramedullary tuberculous granuloma was excised. To our knowledge, this is the first report of spinal cord compression occurring from a subdural tuberculous mass.

Peri-tumoural hypoxia in human brain: peroperative measurement of the tissue oxygen tension around malignant brain tumours.

Malignant brain tumours contain focal hypoxic areas that may increase their resistance to chemotherapy and radiotherapy. Following surgical excision, the peri-tumoural area will contain residual viable tumour cells, and this area is therefore the logical site for subsequent therapy. The new bioreductive agents are metabolized under hypoxic conditions to produce a cytotoxic species. Peroperative peri-tumoural micro-polarographic measurements have been made to establish the oxygen environment of this region and to determine whether the hypoxic conditions might allow for bioreductive drug activation. The micro-polarographic method is described and results are presented for "normal" white matter (8 patients) to allow comparison with peri-tumoural brain (8 patients) before and after removal of the tumour. The results suggest that peri-tumoural brain (median pO2 10.8 mmHg, 18% pO2 < 2.5 mmHg) is markedly hypoxic in comparison with the "normal" brain (median pO2 15.3 mmHg, less than 2% < 2.5 mmHg), and that surgery improves peri-tumoural oxygenation towards that of the "normal" white matter. It is concluded that the hypoxic peri-tumoural area can provide the conditions under which bioreductive agents may be activated.

Does tumour related oedema contribute to the hypoxic fraction of human brain tumours?

Focal hypoxia has been demonstrated and is known to contribute to the resistance of malignant brain tumours to radiation and chemotherapy. Using dynamic needle micro-polarography and tissue morphometry on biopsy specimens, the relationship between the effect of oedema on tissue structure and tissue pO2 was investigated in 24 patients undergoing craniotomy for tumour decompression. An inverse correlation (r = -0.84) was found for intercapillary distance and pO2 levels in peritumoural white matter, but this was less marked (r = -0.22) in tumour, probably as a result of sampling difficulties from tissue heterogeneity. Comparison of maximum pO2 levels in oedematous peritumoural white matter with those in tumour suggests that peritumoural oedema is unlikely to contribute to tumour hypoxia.

Acute perforated duodenal ulcer is not associated with Helicobacter pylori infection.

Most patients with chronic duodenal ulcer disease have Helicobacter pylori infection and eradicating it considerably reduces the relapse rate. The prevalence of H pylori in 80 patients (mean age = 52 years, range 17-85) presenting with acute perforated duodenal ulcer was examined and compared with age and sex matched hospital control patients. H pylori state was assessed by serum anti-H pylori IgG (Helico-G kit, Porton) using a titre of 18 or less as negative with a specificity of 89% and sensitivity of 88%. Only 47% of the perforated duodenal ulcer patients were positive for H pylori and this was similar to the value of 50% in the controls. In 51 of the perforated duodenal ulcer patients 14C-urea breath tests were also performed 4-10 weeks after surgery and this confirmed that only 49% were positive for H pylori. None of these patients had received perioperative drugs that might have eradicated the infection. The H pylori positive and H pylori negative perforated duodenal ulcer patients were similar with respect to age (53, 51), smoking (84%, 83%), and consumption of more than 15 units of alcohol per week (42%, 38%). Duodenal ulcer disease had been diagnosed before acute perforation in only 24% of those with H pylori and also 24% of those without the infection. Regular non-steroidal anti-inflammatory drug (NSAID) use was common in both those with (44%) and without (45%) H pylori. In conclusion, the lack of association of acute perforated duodenal ulcer and H pylori infection suggests that perforated duodenal ulcer has a different pathogenesis from chronic duodenal ulcer disease, and that the first should not be regarded simply as a complication of the second.