Pregnancies in women with Turner syndrome: a retrospective multicentre UK study.

OBJECTIVE: To determine the characteristics and outcomes of pregnancy in women with Turner syndrome. DESIGN: Retrospective 20-year cohort study (2000-20). SETTING: Sixteen tertiary referral maternity units in the UK. POPULATION OR SAMPLE: A total of 81 women with Turner syndrome who became pregnant. METHODS: Retrospective chart analysis. MAIN OUTCOME MEASURES: Mode of conception, pregnancy outcomes. RESULTS: We obtained data on 127 pregnancies in 81 women with a Turner phenotype. All non-spontaneous pregnancies (54/127; 42.5%) were by egg donation. Only 9/31 (29%) pregnancies in women with karyotype 45,X were spontaneous, compared with 53/66 (80.3%) pregnancies in women with mosaic karyotype 45,X/46,XX (P < 0.0001). Women with mosaic karyotype 45,X/46,XX were younger at first pregnancy by 5.5-8.5 years compared with other Turner syndrome karyotype groups (P < 0.001), and more likely to have a spontaneous menarche (75.8% versus 50% or less, P = 0.008). There were 17 miscarriages, three terminations of pregnancy, two stillbirths and 105 live births. Two women had aortic dissection (2.5%); both were 45,X karyotype with bicuspid aortic valves and ovum donation pregnancies, one died. Another woman had an aortic root replacement within 6 months of delivery. Ten of 106 (9.4%) births with gestational age data were preterm and 22/96 (22.9%) singleton infants with birthweight/gestational age data weighed less than the tenth centile. The caesarean section rate was 72/107 (67.3%). In only 73/127 (57.4%) pregnancies was there documentation of cardiovascular imaging within the 24 months before conceiving. CONCLUSIONS: Pregnancy in women with Turner syndrome is associated with major maternal cardiovascular risks; these women deserve thorough cardiovascular assessment and counselling before assisted or spontaneous pregnancy managed by a specialist team. TWEETABLE ABSTRACT: Pregnancy in women with Turner syndrome is associated with an increased risk of aortic dissection.

Meningioma: A Review of Epidemiology, Pathology, Diagnosis, Treatment, and Future Directions.

Meningiomas are the most common intracranial tumor, making up more than a third of all primary central nervous system (CNS) tumors. They are mostly benign tumors that can be observed or preferentially treated with gross total resection that provides good outcomes. Meningiomas with complicated histology or in compromising locations has proved to be a challenge in treating and predicting prognostic outcomes. Advances in genomics and molecular characteristics of meningiomas have uncovered potential use for more accurate grading and prediction of prognosis and recurrence. With the study and detection of genomic aberrancies, specific biologic targets are now being trialed for possible management of meningiomas that are not responsive to standard surgery and radiotherapy treatment. This review summarizes current epidemiology, etiology, molecular characteristics, diagnosis, treatments, and current treatment trials.

Preparing for animal health emergencies: considerations for economic evaluation.

Livestock production systems and the societies in which they are embedded face a set of risks presented by infectious diseases and natural and human-made disasters which compromise animal health. Within this set, threats are posed by natural, deliberate and accidental actions that can cause sudden changes in animal health status, requiring the allocation of additional resources to manage animal health. Determining the benefit of preparing for such emergencies is a challenge when the total set of risks includes the unknown. Any method for analysing the economic costs and benefits of animal health emergencies must not only accommodate this uncertainty, but make it a central feature of the analysis. Cost-benefit analysis is a key approach to economically evaluating animal health interventions. However, the value of this approach in dealing with uncertainty is often called into question. This paper makes the case that, by restricting the outcomes of an emergency event to specified states of nature, boundaries can be placed on the uncertainty space, allowing cost-benefit analysis to be performed. This method, which merges state-contingent analysis with cost-benefit analysis, is presented here. Further discussion on the economic characteristics of emergency events, and the nature of the threats posed to animal health systems, is also provided.

Les systèmes de production animale et les sociétés dans lesquelles ils s'inscrivent doivent faire face à une série de risques associés à des maladies infectieuses ou à des catastrophes d'origine naturelle ou anthropique, qui représentent une menace pour la santé animale. Parmi ces risques, certaines menaces résultant d'actions naturelles, délibérées ou accidentelles peuvent modifier de manière drastique la situation sanitaire des cheptels et imposer d'allouer des ressources supplémentaires à la gestion de la santé animale. Il est difficile de déterminer à l'avance les bénéfices apportés par la préparation aux urgences dès lors que la série complète des risques à envisager comporte des éléments inconnus. Les méthodes d'analyse des coûts et des bénéfices économiques appliquées aux urgences de santé animale doivent non seulement tenir compte de cette incertitude, mais la placer au cœur de l'analyse. L'analyse coûts-bénéfices est une méthode clé pour évaluer les interventions de santé animale dans une perspective économique. Néanmoins, la capacité de cette méthode à traiter l'incertitude est souvent mise en cause. Les auteurs soutiennent qu'en limitant l'analyse des répercussions d'une situation d'urgence à certains états spécifiques de la nature, il devient possible de poser des bornes à l'étendue de l'incertitude, ce qui permet de réaliser une analyse couts-bénéfices. Ils présentent cette méthode, qui consiste à combiner l'analyse des incertitudes dépendantes d'un état de choses donné (state-contingent analysis), avec une analyse coûts-bénéfices. Ils examinent ensuite les caractéristiques économiques des situations d'urgence ainsi que la nature des menaces que ces dernières font peser sur les systèmes de santé animale.

Los sistemas de producción pecuaria y las sociedades en las que están inscritos afrontan una serie de riesgos derivados de enfermedades infecciosas y de desastres de origen natural y humano que ponen en peligro la sanidad animal. Dentro de esta panoplia de riesgos están las amenazas derivadas de sucesos naturales o actos deliberados o accidentales que puedan inducir un cambio repentino de la situación zoosanitaria y exigir recursos adicionales para gestionarla. La determinación de los beneficios que pueda traer consigo la preparación para tales emergencias no es tarea fácil, cuando «lo desconocido¼ forma parte del conjunto de riesgos que se afrontan. Todo método encaminado a analizar los costos económicos y eventuales beneficios en el ámbito de las emergencias zoosanitarias debe no solo integrar esta incertidumbre, sino hacer de ella el elemento central del análisis. El análisis de la relación costo-beneficio es un procedimiento clave para evaluar económicamente las intervenciones de sanidad animal, aunque a menudo se cuestiona su utilidad o idoneidad para manejar la incertidumbre. Los autores postulan que, restringiendo los resultados de un suceso de emergencia a un conjunto especificado de estados de la naturaleza, es posible delimitar el espacio de incertidumbre y, con ello, efectuar un análisis de costos-beneficios. Los autores presentan este método, que consiste en combinar el análisis de las incertidumbres dependientes de un determinado estado de cosas (state-contingent analysis) y el análisis de la relación costo-beneficio. También se detienen a examinar las características económicas de los sucesos de emergencia y el tipo de amenazas que pesan sobre los sistemas de sanidad animal.

The pros and cons of animal health harmonisation.

It has been argued that the global harmonisation of animal health procedures, regulations and responses will improve animal health and provide economic benefits. Harmonisation of regulations can be driven by trade reform, such as multilateral or bilateral agreements, or as a response to private quality assurance programmes. At an international level, trade reform is currently focused on reducing the costs of trading between countries. To achieve this, bilateral agreements, where possible, are harmonising regulations throughout all sectors of the economy. However, as with any new developments, there are both positive and negative outcomes that should be explored to understand the net effect of these changes on animal health, the economy and society. In this article, the authors debate the economic foundations of harmonisation, explore alternative methods to achieve it, and discuss its pros and cons to more fully understand the opportunity costs from countries adopting the same level of risk to animal health.

Il a souvent été avancé qu'en matière de santé animale, l'harmonisation des procédures, des réglementations et des interventions à l'échelle mondiale améliore la situation zoosanitaire globale tout en apportant des bénéfices économiques aux pays. Une telle harmonisation réglementaire peut être le fruit d'une réforme du commerce, notamment par le biais d'accords multilatéraux ou bilatéraux, ou bien constituer une réponse aux programmes d'assurance qualité privés. Au niveau international, la réforme du commerce est actuellement centrée sur la réduction des coûts qu'il entraîne pour les pays. Dans cette perspective, des accords bilatéraux sont conclus chaque fois que possible afin d'harmoniser les réglementations dans tous les secteurs de l'économie. Néanmoins, comme dans toute évolution nouvelle, il en résulte des retombées aussi bien positives que négatives qu'il convient d'analyser afin de bien comprendre l'incidence nette de ces changements sur la santé animale, l'économie et la société. Après avoir débattu des fondements économiques de l'harmonisation, les auteurs examinent les méthodes alternatives qui permettent d'obtenir le même résultat ; ils font aussi le point sur les avantages et les inconvénients de l'harmonisation afin de mieux comprendre le coût d'opportunité qu'elle induit pour les pays adoptant le même niveau de risque en santé animale.

Se ha postulado que la armonización mundial de los procedimientos, reglamentos y respuestas en materia de sanidad animal redundará en un mejor estado sanitario de los animales y reportará beneficios económicos. El impulso para proceder a una armonización reglamentaria puede tener su origen en una reforma del comercio, a raíz por ejemplo de acuerdos multilaterales o bilaterales, o responder a programas privados de garantía de la calidad. A escala internacional, la reforma de los mecanismos comerciales apunta ahora básicamente a reducir los costos del comercio entre países. Para lograrlo se suscriben acuerdos bilaterales que, cuando es posible, entrañan una armonización reglamentaria en todos los sectores de la economía. Sin embargo, como ocurre con todas las novedades, ello tiene repercusiones positivas y negativas, que conviene analizar para aprehender el efecto neto de estos cambios en la sanidad animal, la economía y la sociedad. Los autores examinan los fundamentos económicos de la armonización, plantean métodos alternativos para llevarla adelante y dan cuenta de sus ventajas e inconvenientes para conocer mejor los costos de oportunidad que trae consigo la adopción de un mismo nivel de riesgo zoosanitario por parte de los países.

Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma.

INTRODUCTION: Glioblastoma and anaplastic astrocytoma are two of the most aggressive and common glioma malignancies in adults. These high-grade gliomas (HGG) universally recur despite aggressive treatment modalities and have a median overall survival (mOS) of approximately 14 months from initial diagnosis. Upon recurrence, there is no standard of care and these patients have a dismal prognosis of around 9 months at time of recurrence. Areas covered: In this article, we assess the newly published phase I data of Toca 511 and Toca FC, a two-drug combination therapy for recurrent HGG (rHGG) tumors, for effectiveness and safety. Expert opinion: These early studies provide very encouraging results for Toca 511 and Toca FC in rHGG. This therapy had a response rate of 11.3% and a mOS of 11.9 months in 56 patients, an improvement compared to historical controls. Furthermore, all responders were complete responses after extended follow-up. The drug is well tolerated for most patients. Responders tended to be young and have high-performance scores prior to beginning therapy, but more studies are necessary to understand the patient profile that receives the most benefit. Randomized-controlled trials are warranted for Toca 511 and Toca FC to confirm drug efficacy.

The utility of anti-Müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer.

AIM: Chemotherapy results in permanent loss of ovarian function in some premenopausal women. Accurate identification in women with hormone-sensitive early breast cancer (eBC) would allow optimisation of subsequent endocrine treatment. We sought to assess whether analysis of anti-Müllerian hormone (AMH) using a sensitive automated assay could identify women who would not regain ovarian function after chemotherapy. METHODS: Data from women in the Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION) trial of goserelin (a gonadotrophin-releasing hormone (GnRH) analogue) for ovarian protection were analysed. Women were assessed for premature ovarian insufficiency (POI: amenorrhoea with elevated follicle-stimulating hormone (FSH)) at 24 months after diagnosis. The accuracy of AMH for the diagnosis of POI and its prediction from measurement at the end of chemotherapy was calculated. RESULTS: AMH below the level of detection showed good diagnostic accuracy for POI at 24 months (n = 73) with receiver operating characteristic (ROC) area under the curve of 0.86, sensitivity 1.0 and specificity 0.73 at the assay limit of detection. In women aged >40 at diagnosis who did not receive goserelin, AMH measured at end of chemotherapy also gave good prediction of POI at 24 months (area under the curve (AUC) 0.89 95% CI 0.75-1.0, n = 32), with sensitivity 0.91, specificity 0.82, diagnostic odds ratio (DOR) 42.8. FSH gave slightly lower AUC, and specificity was low at 0.55. Age but not tamoxifen impacted on AMH levels. CONCLUSION: Using this sensitive AMH assay, the finding of an undetectable AMH level in women aged >40 at the end of chemotherapy for eBC gave a good prediction that ovarian function would not return. This may allow alterations in post-chemotherapy endocrine management.

Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis.

STUDY QUESTION: Can live birth be accurately predicted following surgical resection of moderate-severe (Stage III-IV) endometriosis? SUMMARY ANSWER: Live births can accurately be predicted with the endometriosis fertility index (EFI), with adnexal function being the most important factor to predict non-assisted reproductive technology (non-ART) fertility or the requirement for ART (www.endometriosisefi.com). WHAT IS KNOWN ALREADY: Fertility prognosis is important to many women with severe endometriosis. Controversy persists regarding optimal post-operative management to achieve pregnancy and the counselling of patients regarding duration of conventional treatments before undergoing ART. The EFI is reported to correlate with expectant management pregnancy rate, although external validation has been performed without specifically addressing fertility in women with moderate and severe endometriosis. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 279 women from September 2001 to June 2016. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We included women undergoing laparoscopic resection of Stage III-IV endometriosis who attempted pregnancy post-operatively. The EFI was calculated based on detailed operative reports and surgical images. Fertility outcomes were obtained by direct patient contact. Kaplan-Meier model, log rank test and Cox regression were used for analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The follow-up rate was 84% with a mean duration of 4.1 years. A total of 147 women (63%) had a live birth following surgery, 94 of them (64%) without ART. The EFI was highly associated with live births (P < 0.001): for women with an EFI of 0-2 the estimated cumulative non-ART live birth rate at five years was 0% and steadily increased up to 91% with an EFI of 9-10, while the proportion of women who attempted ART and had a live birth, steadily increased from 38 to 71% among the same EFI strata (P = 0.1). A low least function score was the most significant predictor of failure (P = 0.003), followed by having had a previous resection (P = 0.019) or incomplete resection (P = 0.028), being older than 40 compared to <35 years of age (P = 0.027), and having leiomyomas (P = 0.037). LIMITATIONS REASONS FOR CAUTION: The main limitation of this study is its retrospective design. Imprecision was higher with low EFI due to smaller sample size in this subgroup. Finally, the EFI is somewhat subjective and could be prone to intra- and inter-observer variations. WIDER IMPLICATIONS OF THE FINDINGS: Women with a high EFI score have excellent fertility prognosis and may be advised to try to become pregnant with timed intercourse compared to women with a low score, for which prompt referral to ART seems more reasonable. Other prognostic factors can be used to guide the management of women with an intermediate EFI score. These data follow women over many years post-resection and represent longitudinal fertility data rarely demonstrated in such a cohort. The location and impact of lesions on the ability of the adnexa to function seems crucial for the fertility prognosis and should be further investigated. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the GRACE Research funds. S.M.-L. is the recipient of a Training Award from the Fonds de Recherche Quebec-Sante. D.A. is the primary author of the Endometriosis Fertility Index. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The importance of fixed costs in animal health systems.

In this paper, the authors detail the structure and optimal management of health systems as influenced by the presence and level of fixed costs. Unlike variable costs, fixed costs cannot be altered, and are thus independent of the level of veterinary activity in the short run. Their importance is illustrated by using both single-period and multi-period models. It is shown that multi-stage veterinary decision-making can often be envisaged as a sequence of fixed-cost problems. In general, it becomes clear that, the higher the fixed costs, the greater the net benefit of veterinary activity must be, if such activity is to be economic. The authors also assess the extent to which it pays to reduce fixed costs and to try to compensate for this by increasing variable costs. Fixed costs have major implications for the industrial structure of the animal health products industry and for the structure of the private veterinary services industry. In the former, they favour market concentration and specialisation in the supply of products. In the latter, they foster increased specialisation. While cooperation by individual farmers may help to reduce their individual fixed costs, the organisational difficulties and costs involved in achieving this cooperation can be formidable. In such cases, the only solution is government provision of veterinary services. Moreover, international cooperation may be called for. Fixed costs also influence the nature of the provision of veterinary education.

Les auteurs de cet article décrivent en détail la structure et la gestion optimale des systèmes de santé, telles que les influencent l'existence et le volume des coûts fixes. Contrairement aux coûts variables, les coûts fixes ne sont pas modulables et sont donc indépendants du volume d'activité du secteur vétérinaire à court terme. Leur importance est illustrée par l'utilisation simultanée de modèles couvrant une période unique et de modèles multi-périodiques. Il est démontré qu'en santé animale, le processus décisionnel par étapes peut souvent être envisagé comme une séquence de problèmes liés aux coûts fixes. En général, il apparaît clairement que plus les coûts fixes sont élevés, plus grand doit être le bénéfice net dégagé par les prestations vétérinaires, si l'on veut que celles-ci soient rentables. Les auteurs évaluent également l'intérêt éventuel de réduire les coûts fixes en essayant de compenser cette baisse par une augmentation des coûts variables. Les coûts fixes ont des répercussions structurelles majeures sur l'activité du secteur des produits de santé animale ainsi que sur les prestations vétérinaires du secteur privé. Dans le secteur des produits de santé animale, les coûts fixes favorisent la concentration des marchés et la spécialisation de l'offre. Dans le secteur de l'exercice vétérinaire privé, ils incitent à une spécialisation accrue. Si la coopération individuelle des éleveurs peut contribuer à réduire leurs charges fixes à l'échelle individuelle, les contraintes organisationnelles et les coûts induits par une telle coopération peuvent s'avérer redoutables. Dans de telles configurations, la seule solution consiste à confier la prestation des services vétérinaires au secteur public. Il peut aussi être fait appel à la coopération internationale. Les coûts fixes influencent également la nature de l'offre de formation en médecine vétérinaire.

Los autores exponen en detalle la estructura y la gestión óptima de los sistemas sanitarios en aquellos aspectos que se ven influidos por la presencia de costos fijos y por su cuantía. A diferencia de los costos variables, los fijos no pueden ser modificados y por lo tanto son, a corto plazo, independientes del nivel de actividad veterinaria. El uso de modelos relativos a un periodo único y a periodos múltiples pone de manifiesto la importancia que revisten los costos fijos. Los autores explican que el proceso de adopción de decisiones veterinarias, que discurre en varias etapas, puede ser entendido a menudo como una secuencia de problemas ligados a los costos fijos. En general queda claro que, cuanto más elevados sean los costos fijos de la actividad veterinaria, mayor beneficio neto debe deparar esta para ser rentable. Los autores también valoran en qué medida resulta rentable disminuir los costos fijos y tratar de compensar esta reducción con un aumento de los costos variables. Los costos fijos influyen sobremanera en la estructura de actividad económica del sector de los productos de sanidad animal y en la estructura de la prestación privada de servicios veterinarios. En el primer caso, favorecen la concentración del mercado y la especialización en el suministro de determinados productos. En el segundo, potencian un mayor grado de especialización. Aunque la cooperación entre los ganaderos puede ayudar a reducir sus costos fijos individuales, este tipo de cooperación entraña enormes dificultades y costos organizativos. En tales casos, la única solución reside en la prestación de servicios veterinarios desde instancias oficiales. Por otro lado, también cabe recurrir a la cooperación internacional. Los costos fijos influyen asimismo en el tipo de enseñanza de la veterinaria que se imparte.

Management of Glioblastoma Multiforme in Elderly Patients: A Review of the Literature.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, occurs most commonly in individuals older than 65 years of age, and is universally fatal. Increasing age compounds the poor prognosis of GBM, as elderly patients have markedly worse outcomes than younger patients. However, many of the studies previously investigating optimal treatment regimens exclude patients older than the age of 65 years and thus may not represent the best approaches to ensuring prolonged survival with preserved quality of life. This review aims to highlight the current literature on surgical and medical management, including our own experience, for GBM in the elderly patients, and to provide rational treatment approaches for a vulnerable, often-overlooked, patient population.

GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial.

BACKGROUND: Chemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women's health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI. PATIENTS AND METHODS: This was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I-IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI. RESULTS: A total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Müllerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups. CONCLUSION: This study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.

Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas.

Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas.

A randomised trial of secondary prophylaxis using granulocyte colony-stimulating factor ('SPROG' trial) for maintaining dose intensity of standard adjuvant chemotherapy for breast cancer by the Anglo-Celtic Cooperative Group and NCRN.

BACKGROUND: Guidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI. PATIENTS AND METHODS: Adult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups. RESULTS: Most regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P < 0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF. CONCLUSIONS: Secondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.

Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours.

PURPOSE: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. METHODS: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. RESULTS: In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C (ss,max), 36 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 20 mg increased by 21 % (94 % CI 9-35 %) and 26 % (94 % CI 10-43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C (ss,max) and 41 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 45 mg decreased by 39 % (90 % CI 34-43 %) and 23 % (90 % CI 16-30 %), respectively, in the presence of rifampicin. gMean ratios for AUC(ss) and C (ss,max) were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC(ss) and C (ss,max) was observed. The safety profile of cediranib was similar to that reported previously. CONCLUSIONS: Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.

Rindopepimut: an evidence-based review of its therapeutic potential in the treatment of EGFRvIII-positive glioblastoma.

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is universally fatal. Despite surgical resection, radiotherapy, and systemic chemotherapy, the median overall survival is less than 15 months. As current therapies are not tumor-specific, treatment commonly results in toxicity. The epidermal growth factor receptor variant III (EGFRvIII) is a naturally occurring mutant of EGFR and is expressed on approximately 20% to 30% of GBMs. As it is not expressed on normal cells, it is an ideal therapeutic target. Rindopepimut is a peptide vaccine which elicits EGFRvIII-specific humoral and cellular immune responses. Phase I and II clinical trials have demonstrated significantly higher progression-free and overall survival times in vaccinated patients with EGFRvIII-expressing GBM tumors. Side effects are minimal and mainly consist of hypersensitivity reactions. Due to the efficacy and safety of rindopepimut, it is a promising therapy for patients with GBM. Currently, rindopepimut is undergoing clinical testing in an international Phase III trial for newly diagnosed GBM and a Phase II trial for relapsed GBM.

Marked response of gliomatosis cerebri to temozolomide and whole brain radiotherapy.

Gliomatosis cerebri (GC) represents an unfortunate, rare variant of glioma with a very poor prognosis. Given this lesion's rarity, little information exists on appropriate treatment options. The diffuse, infiltrative nature of GC precludes any surgical resection and limits therapy. Because of the improved survival seen with the use of temozolomide (TMZ) in malignant glioma, a rigorous systematic review of the published literature was performed to ascertain the benefit of TMZ in GC. We identified all GC cases in the literature where there was enough information to ascertain a clear response to a specific chemoradiotherapeutic treatment. In addition to our experience with a recent case, we have identified 61 patients with GC in the published literature who demonstrated a positive radiographic or clinic response after treatment. Statistical analysis of survival was performed by Kaplan-Meier analysis. A positive radiographic and clinical response was seen in patients ranging in age from 4 to 84 years. Overall median survival in patients diagnosed with GC who demonstrated a response after treatment was 25 months, with 1- and 2-year survival rates of 89% and 55%, respectively. The most common treatment regimens for responders included TMZ alone (26.2%), external whole-brain radiotherapy (WBRT) (26.2%), and concomitant TMZ and WBRT (20%). Our patient was treated with concomitant TMZ (150 mg/m(2)/day over 5 days) and WBRT (50 Gy) and has remained with a complete radiographic response after 36 months. In conclusion, patients with GC confirmed by surgical biopsy should be aggressively treated with concomitant TMZ and WBRT, as marked responses have been seen, and this appears to offer overall survival benefit.