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.

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.

Testing Taxonomic Predictivity of Foliar and Tuber Resistance to Phytophthora infestans in Wild Relatives of Potato.

Potato late blight, caused by the oomycete phytopathogen Phytophthora infestans, is a devastating disease found in potato-growing regions worldwide. Long-term management strategies to control late blight include the incorporation of host resistance to predominant strains. However, due to rapid genetic changes within pathogen populations, rapid and recurring identification and integration of novel host resistance traits is necessary. Wild relatives of potato offer a rich source of desirable traits, including late blight resistance, but screening methods can be time intensive. We tested the ability of taxonomy, ploidy, crossing group, breeding system, and geography to predict the presence of foliar and tuber late blight resistance in wild Solanum spp. Significant variation for resistance to both tuber and foliar late blight was found within and among species but there was no discernable predictive power based on taxonomic series, clade, ploidy, breeding system, elevation, or geographic location. We observed a moderate but significant correlation between tuber and foliar resistance within species. Although previously uncharacterized sources of both foliar and tuber resistance were identified, our study does not support an assumption that taxonomic or geographic data can be used to predict sources of late blight resistance in wild Solanum spp.

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.

Use of tissue expander in pelvic Ewing's sarcoma treated with radiotherapy.

INTRODUCTION: The local treatment option for pelvic Ewing sarcoma (ES) remains uncertain and challenging as surgery is often disabling while radiotherapy alone has a higher risk of local recurrence but not necessarily a worse survival. The aim is to analyse the outcome of patients with pelvic ES after radiotherapy as the primary local treatment in combination with a temporary intrapelvic surgically placed tissue expander (TE) to reduce bowel complications. MATERIALS AND METHODS: 20 patients were retrospectively analysed. All patients had neoadjuvant and adjuvant chemotherapy. We identified survival, time to develop local recurrence and metastasis, dose of radiotherapy administered, local complications related to the use of the tissue expander and bowel effects of radiotherapy. RESULTS: The median follow-up was 41 months. 14 patients were stage IIb and six stage III. There were no problems after insertion of the TE and only one patient who developed mild diarrhoea. Local recurrence occurred in six patients. At the last follow-up 12 patients have died from sarcoma, five are disease free and three have had recurrent disease. CONCLUSIONS: In this paper we reviewed pelvic Ewing sarcoma with all the special considerations that this entails. We think that tissue expander can be safely used when radiotherapy is chosen to treat pelvic ES. It does appear to prevent bowel problems and is a low morbidity procedure. New treatment approaches should be considered to give a chance of cure to those patients with "bad prognostic" pelvic ES.

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 randomised controlled trial to evaluate both the role and the optimal fractionation of radiotherapy in the conservative management of early breast cancer.

AIMS: Postoperative radiotherapy is routinely used in early breast cancer employing either 50 Gy in 25 daily fractions (long course) or 40 Gy in 15 daily fractions (short course). The role of radiotherapy and shorter fractionation regimens require validation. MATERIALS AND METHODS: Patients with clinical stage I and II disease were randomised to receive immediate radiotherapy or delayed salvage treatment (no radiotherapy). Patients receiving radiotherapy were further randomised between long (50 Gy in 25 daily fractions) or short (40 Gy in 15 daily fractions) regimens. The primary outcome measure was time to first locoregional relapse. Reported results are at a median follow-up of 16.9 years (interquartile range 15.4-18.8). RESULTS: In total, 707 women were recruited between 1985 and 1992: median age 59 years (range 28-80), 68% postmenopausal, median tumour size 2.0 cm (range 0.12-8.0); 271 patients have relapsed: 110 radiotherapy, 161 no radiotherapy. The site of first relapse was locoregional158 (64%) and distant 87 (36%). There was an estimated 24% reduction in the risk of any competing event (local relapse, distant relapse or death) with radiotherapy (hazard ratio = 0.76; 95% confidence interval 0.65, 0.88). The benefit of radiotherapy treatment for all competing event types was statistically significant (X(Wald)(2) = 36.04, P < 0.001). Immediate radiotherapy reduced the risk of locoregional relapse by 62% (hazard ratio = 0.38; 95% confidence interval 0.27, 0.53), consistent across prognostic subgroups. No differences were seen between either radiotherapy fractionation schedules. CONCLUSIONS: This study confirmed better locoregional control for patients with early breast cancer receiving radiotherapy. A radiotherapy schedule of 40 Gy in 15 daily fractions is an efficient and effective regimen that is at least as good as the international conventional regimen of 50 Gy in 25 daily fractions.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

Biological reconstruction after excision, irradiation and reimplantation of diaphyseal tibial tumours using an ipsilateral vascularised fibular graft.

The purpose of this study was to assess the outcome of 15 patients (mean age 13.6 years (7 to 25)) with a primary sarcoma of the tibial diaphysis who had undergone excision of the affected segment that was then irradiated (90 Gy) and reimplanted with an ipsilateral vascularised fibular graft within it. The mean follow-up was 57 months (22 to 99). The mean time to full weight-bearing was 23 weeks (9 to 57) and to complete radiological union 42.1 weeks (33 to 55). Of the 15 patients, seven required a further operation, four to obtain skin cover. The mean Musculoskeletal Society Tumor Society functional score at final follow-up was 27 out of 30 once union was complete. The functional results were comparable with those of allograft reconstruction and had a similar rate of complication. We believe this to be a satisfactory method of biological reconstruction of the tibial diaphysis in selected patients.

Prognostic factors and metastatic patterns in primary myxoid/round-cell liposarcoma.

Background. This study aimed to investigate prognostic factors for patients with myxoid/round-cell liposarcoma (MRCLS), in particular the significance of the round cell component, and to identify metastatic patterns as well as possibly suggest a suitable strategy for followup. Methods. Clinical, morphologic, and follow-up data from 160 patients with MRCLS was reviewed and statistically analysed. Results. Of 130 tumours with the round cell component evaluated, 61 had no round cell component, 27 had <5% round cell component, and 42 had >5%. All patients underwent surgical excision, 15 requiring amputation. 107 patients received adjuvant radiotherapy. Local recurrence occurred in 19 patients (12%), predominantly in patients with marginal or intralesional margins and a round cell component. Overall disease specific survival was 75% at 5 years and 56% at 10 years and was related to the proportion of round cell component. Of 52 patients who developed metastases, 38 (73%) had purely extrapulmonary metastases. We could not identify any factors predicting the site of metastases developing. Conclusions. The occurrence of any round cell component is the most important adverse prognostic factor for patients with MRCLS; patients with >5% round cell component are at higher risk of local recurrence, metastasis and tumour-related death and should be considered for adjuvant radiotherapy and possibly chemotherapy. The best method of monitoring extrapulmonary metastases remains to be established.

The 'other' bone sarcomas: prognostic factors and outcomes of spindle cell sarcomas of bone.

We aimed to identify the incidence, outcome and prognostic factors associated with spindle cell sarcomas of bone (SCSB). We studied 196 patients with a primary non-metastatic tumour treated with the intent to cure. The results were compared with those of osteosarcoma patients treated at our hospital during the same period. The overall incidence of SCSB was 7.8% of all patients with a primary bone sarcoma. The five- and ten-year survival rates were 67.0% and 60.0%, respectively, which were better than those of patients with osteosarcoma treated over the same period. All histological subtypes had similar outcomes. On univariate analysis, factors that were significantly associated with decreased survival were age > 40 years, size > 8 cm, the presence of a pathological fracture, amputation, involved margins and a poor response to pre-operative chemotherapy. Multivariate analyses showed that age > 65 years, amputation and involved margins were all statistically significant prognostic factors. Involved margins and poor response to pre-operative chemotherapy were associated with an increased risk of local recurrence. SCSB has a better prognosis than osteosarcoma when matched for age. Most prognostic factors for osteosarcoma also seem to apply to SCSB. Patients with SCSB should be treated in the same way as patients of the same age with osteosarcoma.

A test of taxonomic and biogeographic predictivity: resistance to Potato virus Y in wild relatives of the cultivated potato.

A major justification for taxonomic research is its assumed ability to predict the presence of traits in a group for which the trait has been observed in a representative subset of the group. Similarly, populations in similar environments are expected to be more alike than populations in divergent environments. Consequently, it is logical to assume that taxonomic relationships and biogeographical data have the power to predict the distribution of disease resistance phenotypes among plant species. The objective of this study was to test predictivity in a group of widely distributed wild potato species, based on hypotheses that closely related organisms (taxonomy) or organisms from similar environments (biogeography) share resistance to a simply inherited trait (Potato virus Y [PVY]). We found that wild potato species with an endosperm balance number (EBN) of 1 (a measure of cross compatibility) shared resistances to PVY more than species with different EBN values. However, a large amount of variation was found for resistance to PVY among and within species. We also found that populations from low elevations were more resistant than those from high elevations. Because PVY is vectored by aphids, we speculate that the distribution of aphids may determine the level of selection pressure for PVY resistance.

Oncological outcomes of patients with Ewing's sarcoma: is there a difference between skeletal and extra-skeletal Ewing's sarcoma?

The aim of this study was to identify whether there was any difference in patient, tumour, treatment or outcome characteristics between patients with skeletal or extra-skeletal Ewing's sarcoma. We identified 300 patients with new primary Ewing's sarcoma diagnosed between 1980 and 2005 from the centres' local database. There were 253 (84%) with skeletal and 47 (16%) with extra-skeletal Ewing's sarcomas. Although patients with skeletal Ewing's were younger (mean age 16.8 years) than those with extra-skeletal Ewing's sarcoma (mean age 27.5 years), there was little difference between the groups in terms of tumour stage or treatment. Nearly all the patients were treated with chemotherapy and most had surgery. There was no difference in the overall survival of patients with skeletal (64%) and extra-skeletal Ewing's sarcoma (61%) (p = 0.85), and this was also the case when both groups were split by whether they had metastases or not. This large series has shown that the oncological outcomes of Ewing's sarcoma are related to tumour characteristics and patient age, and not determined by whether they arise in bone or soft tissue.

Chemotherapy for breast cancer (Review).

The use of cytotoxic chemotherapy in both advanced and early stage breast cancer has made significant progress in the last 10 years with several landmark studies identifying clear survival benefits for newer therapies. In spite of these developments the optimal approach for any specific patient can not be determined from a literature review or decision-making algorithm alone. Treatment choices are predominantly based on practice determined by individual or collective experience and the historical development of treatment within a locality. The improvement in the understanding of the molecular biological basis of breast cancer provides possible targets for novel therapies. Personalised therapies for breast cancer based on the molecular characteristics of the tumour could improve the risk: benefit ratio of current therapies. Increased improvements in the use of a panel of biomarkers will thus not only move us towards tailored therapies but will also spare a group of patients that do not benefit from adjuvant chemotherapy. At the same time a better understanding of tumour biology will also streamline the development of new regimens for those who are unlikely to benefit from existing drugs. This review will focus on the evidence for the use of chemotherapy and highlight advances in chemotherapy treatments with the addition of new and novel drugs marching into our clinics as standard treatments based on evidence from clinical trials and from a better understanding of tumour biology that has transformed the outlook in breast cancer in both the adjuvant and metastatic setting.

Giant cell tumour of the sacrum: a suggested algorithm for treatment.

To investigate the outcome of our management of patients with giant cell tumour of the sacrum and draw lessons from this. A retrospective review of medical records and scans for all patients treated at our unit over the past 20 years with a giant cell tumour of the sacrum. Of the 517 patients treated at our unit for giant cell tumour over the past 20 years, only 9 (1.7%) had a giant cell tumour in the sacrum. Six were female, three male with a mean age of 34 (range 15-52). All, but two tumours involved the entire sacrum and there was only one purely distal to S3. The mean size was 10 cm and the most common symptom was back or buttock pain. Five had abnormal neurology at diagnosis, but only one presented with cauda equina syndrome. The first four patients were treated by curettage alone, but two patients had intraoperative cardiac arrests and although both survived all subsequent curettages were preceded by embolisation of the feeding vessels. Of the seven patients who had curettage, three developed local recurrence, but all were controlled with a combination of further embolisation, surgery or radiotherapy. One patient elected for treatment with radiotherapy and another had excision of the tumour distal to S3. All the patients are alive and only two patients have worse neurology than at presentation, one being impotent and one with stress incontinence. Three patients required spinopelvic fusion for sacral collapse. All patients are mobile and active at a follow-up between 2 and 21 years. Giant cell tumour of the sacrum can be controlled with conservative surgery rather than subtotal sacrectomy. The excision of small distal tumours is the preferred option, but for larger and more extensive tumours conservative management may well avoid morbidity whilst still controlling the tumour. Embolisation and curettage are the preferred first option with radiotherapy as a possible adjunct. Spinopelvic fusion may be needed when the sacrum collapses.

Ten things your emergency department should consider to prepare for pandemic influenza.

Pandemic influenza remains a potential major threat to global public health. It is essential for emergency departments to be involved in planning for the management of such a major event. It is also important for emergency departments to be clear on their internal arrangements for staff and for patient care. This paper outlines 10 suggestions for UK emergency departments based on the recent experience of emergency departments in Hong Kong and elsewhere.

A test of taxonomic predictivity: resistance to the Colorado potato beetle in wild relatives of cultivated potato.

Wild relatives of potato offer a tremendous germplasm resource for breeders. Because the germplasm base of potato is so broad and diverse, we have undertaken a series of studies to determine whether we can predict the distribution of valuable genes in wild Solanum species based on taxonomic or biogeographic data. This is the third study in the series. Resistance to defoliation by Colorado potato beetle, Leptinotarsa decemlineata Say, larvae was evaluated in 156 accessions of 41 wild Solanum species. The highest frequencies of resistant accessions were found in diploid species with an endosperm balance number of 1. In contrast to previous studies on resistance to foliar fungal pathogens, there was little variability in defoliation scores among plants within an accession and among accessions within a species, at least for the most resistant species. There was no strong association of Colorado potato beetle resistance in wild potato species to biogeographic data. Resistance was confirmed in species previously characterized by high levels of glycoalkaloids or dense glandular trichomes. However, we have identified additional species with resistance to the Colorado potato beetle. Mechanisms of resistance are being studied in these species and attempts will be made to introgress them into the cultivated potato.

A test of taxonomic predictivity: resistance to early blight in wild relatives of cultivated potato.

Host plant resistance offers an attractive method of control for early blight (caused by the foliar fungus Alternaria solani), a widespread disease that appears annually in potato crops worldwide. We tested the assumed ability of taxonomy to predict the presence of early blight resistance genes in wild Solanum species for which resistance was observed in related species. We also tested associations to ploidy, crossing group, breeding system, and geography. As in a prior study of Sclerotinia sclerotiorum (white mold) resistance, tremendous variation for resistance to early blight was found to occur within and among species. There was no discernable relationship between the distribution of resistant phenotypes and taxonomic series (based on an intuitive interpretation of morphological data), clade (based on a cladistic analysis of plastid DNA data), ploidy, breeding system, geographic distance, or climate parameters. Species and individual accessions with high proportions of early blight resistant plants were identified, but high levels of inter- and intra-accession variability were observed. Consequently, the designation of species or accessions as resistant or susceptible must take this variation into account. This study calls into question the assumption that taxonomic or geographic data can be used to predict sources of early blight resistance in wild Solanum species.