A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

The utility of routine pre-chemotherapy screening with cardiac gated blood pool scan for patients at low risk of anthracycline toxicity.

Background Anthracycline-based chemotherapy is used in many malignancies. Current recommendations by several groups suggest cardiac monitoring prior to and during anthracycline therapy. We aim to review the usefulness of baseline cardiac screening for left ventricular ejection fraction to assess if it had any impact on chemotherapy decisions in patients to be treated with anthracycline-based regimens or any beneficial effect upon outcomes. Methods We conducted a retrospective three-year audit of cancer patients who underwent GBPS prior to anthracycline (doxorubicin) chemotherapy. Subjects were identified via records from the Department of Nuclear Medicine. Pharmacy dispensing records identified those who received doxorubicin. Patient demographics, cancer type, cardiac risk factors, GBPS ejection fraction (EF), and cumulative anthracycline dose were collected. Results From 1 August 2009 to 31 July 2012, 179 patients underwent GBPS pre-doxorubicin chemotherapy. The mean age was 59 years (range 21-89 years), with 51% being males. Only two patients (1.1%) had an abnormal EF < 50%, while 33 patients (18%) had an EF 51-59% and 144 patients (80%) had EF ≥ 60%. The two patients with reduced baseline EF still received anthracycline-based chemotherapy. All 135 patients without any known cardiovascular risk factors had normal EFs. The total number of patients who received anthracycline chemotherapy during the same period was 207. Thus 28 patients (13%) commenced anthracycline without a prior GBPS. Conclusion Only 1.1% of the screened patients had EF < 50%. These two patients still received doxorubicin chemotherapy despite a compromised EF, as their treating clinicians believed that the benefits of chemotherapy outweighed the risk of potential cardiac toxicity. Our audit questions the practice of routine cardiac evaluation pre-anthracycline screening with GBPS. We propose that routine screening only be requested if cardiac risk factors are present.

Predicting distress among people who care for patients living longer with high-grade malignant glioma.

PURPOSE: Caregivers of patients living longer with high-grade malignant glioma (HGG) have the unique challenge of caring for a person who may have cognitive impairment, along with cancer-related issues over a prolonged period of time. This study aims to detail the psychosocial profile of long-term caregivers, to describe their perceptions of the patient's quality of life and to examine predictors of their psychological distress. METHODS: Sixty-nine caregivers (48%) of eligible patients with HGG surviving over 2 years were recruited from two Australian metropolitan tertiary hospitals. Caregivers completed cross-sectional measures of psychological distress (GHQ-12), caregiver impact (FACQ-PC) and patient functional well-being (FACT-Br TOI). Correlational analyses identified factors related to caregiver psychological distress. Those of significance (p ≤ .01) were examined using multiple regression models to determine their predictive value. RESULTS: Caregivers were mostly female (73%), spouses (67%), cohabiting (78%) and were caring for patients surviving a median of 5.9 years since diagnosis. Whilst caregivers overall reported minimal psychological distress, 28% endorsed moderate to severe psychological distress, warranting clinical attention. Caregiver strain and low patient functional well-being both significantly predicted caregiver psychological distress (adjusted R(2) = .35, F(4, 60) = 17.7, p < .001), accounting for a moderate amount (35%) of variance. Other typical factors such as duration of caregiving, performance status, symptom burden and disease or demographic related factors were not predictive. CONCLUSIONS: Psychological distress affects a significant proportion of caregivers of patients living longer with HGG. The presence of caregiver strain and low patient functional well-being are the most important predictors of psychological distress among this cohort of caregivers.

Phylogenetic investigation of the genus Raoiella (Prostigmata: Tenuipalpidae): diversity, distribution, and world invasions.

The genus Raoiella is best known because of the red palm mite, R. indica, a major pest of palms spreading aggressively throughout the Americas. Not much was known about the biology, geographic origins, or evolutionary history of the genus when R. indica emerged as a major invasive pest. This paper attempts to address some of the basic historical questions regarding the palm mite as well as the genus. Molecular characters from COI and 28S regions were used to produce a phylogenetic hypothesis for the genus in an effort to understand its geographic origin. It also uses COI barcode data to delimit several potentially new species discovered by the authors in Australia. Results show a basal split between R. indica and all other Raoiella species, which indicates Africa or the Middle East as the most probable origin of the genus. Additionally, COI data suggests that at least eight new species are represented among the 20 Australian populations included in this study.

External mouthpart morphology in the Tenuipalpidae (Tetranychoidea): Raoiella a case study.

The use of low-temperature scanning electron microscopy (LTSEM) to study external mouthpart morphology in the Tenuipalpidae, in particular the genus Raoiella, has brought some aspects of the mechanics of feeding in this group into question. In addition, an LTSEM study on the specialized feeding behaviour of Raoiella indica Hirst (Tetranychoidea: Tenuipalpidae) revealed host plant use in this species could be affected by stomatal complex morphology.

Surviving glioblastoma and a sense of disconnection.

Given the poor prognosis of glioblastoma, little focus has been placed on the needs of long-term survivors (those alive at least two years following diagnosis). The aim of this project was to explore the lived experience of long-term survivors of glioblastoma using a qualitative approach. Long-term survivors of glioblastoma diagnosed between 1/1/2006-31/12/2016 were identified at the tertiary centre involved. Participants underwent a semi-structured qualitative interview and caregiver dyads were collected if available. Thematic analysis was undertaken where themes were gradually generated from the data alongside data collection and confirmed or contrasted as data collection proceeded. Participants were selected and interviewed until data saturation was reached at 10 interviews. The overarching theme explaining the data was a sense of disconnection, beginning with the shock of diagnosis, and evolving over time, leading survivors to feel disconnected from (1) 'who I was', redefining their work, independence and social self; (2) 'who I am', contributing to social isolation, disavowal, and anxiety and depression; and (3) 'who I could be', reassessing their future. This unique study highlights the acute emotional distress and disconnection that begins with diagnosis and its evolving impact on the lived experience. Clinicians need to consider the emotional impact of survival when managing these patients and adopt a holistic approach, including the early introduction of psychosocial support to patients and their caregivers. Further validation of these findings in a larger cohort is desirable.

Delimiting species boundaries within Dermanyssus Dugès, 1834 (Acari:Dermanyssidae) using a total evidence approach.

The genus Dermanyssus is currently composed of 24 hematophagous mite species and includes the Poultry Red Mite, Dermanyssus gallinae, a serious pest in poultry houses. Morphologically, Dermanyssus species fall into two groups corresponding to Moss'gallinae-group and to hirsutus-group+Microdermanyssus. Species of the gallinae-group exhibit high levels of morphological variability, and are nearly impossible to distinguish. Species of the second group display consistent characters and host associations and are easily distinguishable. Species of the gallinae-group tend to be the major problems in poultry houses and it is unknown whether D. gallinae is the only pest, or if there are numerous cryptic species present in the system. Twenty species of Dermanyssus were tested phylogenetically based on 46 morphological characters. A subset of species, mainly of the gallinae-group, represented each by several populations, was sequenced for two mitochondrial and one nuclear gene regions. This allowed testing their specific status and their interrelationships based and on morphological and molecular characters. The molecular data was analysed separately and in combination with morphological characters. As expected, morphology did a poor job resolving relationships. Molecular data proved more informative. The resulting phylogenetic hypotheses brought some information about interrelationships among species of the gallinae-group showing a split into two main clades. The invasion of human managed environments seems to occur only in taxa within one of the two clades. The host spectrum seems to get enlarged in more derived taxa in the same clade. A delineation of six species within the gallinae-group is provided. Additionally, a key for morphological identification of these species is provided. D. gallinae appears to be the only pest in poultry houses, but is composed of several different and more or less strongly isolated lineages. A new species found from the black swift is described.

Molecular phylogenetic assessment of host range in five Dermanyssus species.

Given that 14 out of the 25 currently described species of Dermanyssus Dugès, 1834, are morphologically very close to each another, misidentifications may occur and are suspected in at least some records. One of these 14 species is the red fowl mite, D. gallinae (De Geer, 1778), a blood parasite of wild birds, but also a pest in the poultry industry. Using molecular phylogenetic tools we aimed to answer two questions concerning host specificity and synanthropicity: (1) is D. gallinae the only species infesting European layer farms?, and (2) can populations of D. gallinae move from wild to domestic birds and vice versa? Mitochondrial cytochrome oxidase I gene sequences were obtained from 73 Dermanyssus populations collected from nests of wild European birds and from poultry farms and these were analyzed using maximum parsimony and Bayesian inference. Mapping of the observed host range on the obtained topology and correlation with behavioural observations revealed that (1) host range is strongly dependent on some ecological parameters (e.g. nest hygiene, exposure to pesticides and predators), that (2) out of five species under test, synanthropic populations were found only in lineages of D. gallinae, and that (3) at least some haplotypes found in wild birds were very close to those found in association with domestic birds.

Molecular profile of long-term survivors of glioblastoma: A scoping review of the literature.

Molecular aberrations of malignancy are becoming widely recognized as important predictive and prognostic markers for treatment response and survival in oncology and have been linked to the discovery of novel treatment targets. This area of research in glioblastoma continues to evolve. The aim of this scoping review was to document the hallmark molecular characteristics of long-term survivors of glioblastoma. MEDLINE, Scopus and EMBASE were searched with core concepts: (1) glioblastoma, (2) long-term survivor and (3) molecular OR mutation. A thematic analysis was undertaken of the 18 included studies. Four main classes of characteristics were obtained: IDH mutation, MGMT methylation, other known characteristics and novel discoveries. While MGMT methylation or the combination with IDH mutation are suggested to be hallmark characteristics, there remains enough uncertainty to suggest further factors may be involved, such as CD34 expression. Further research is required to accurately describe hallmark molecular characteristics of long-term survivors to assist in defining these patients at diagnosis, preventing treatment complications and discovering novel treatments.

Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis.

OBJECTIVES: The aim of the current study was to determine the contribution of interleukin (IL)1 gene cluster polymorphisms previously implicated in susceptibility for ankylosing spondylitis (AS) to AS susceptibility in different populations worldwide. METHODS: Nine polymorphisms in the IL1 gene cluster members IL1A (rs2856836, rs17561 and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel-Haenszel random effects analysis. RESULTS: Strong association was observed with three single nucleotide polymorphisms (SNPs) in the IL1A gene (rs2856836, rs17561, rs1894399, p = 0.0036, 0.000019 and 0.0003, respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4-6%. CONCLUSIONS: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.

Quality assurance of computed and digital radiography systems.

Computed radiography (CR) and digital radiography (DR) are replacing traditional film screen radiography as hospitals move towards digital imaging and picture archiving and communication systems (PACS). Both IPEM and KCARE have recently published quality assurance and acceptance testing guidelines for DR. In this paper, the performance of a range of CR and DR systems is compared. Six different manufacturers are included. Particular attention is paid to the performance of the systems under automatic exposure control (AEC). The patient is simulated using a range of thicknesses of tissue equivalent material. Image quality assessment was based on detector assessment protocols and includes pixel value measures as well as subjective assessment using Leeds Test Objects. The protocols for detector assessment cover a broad range of tests and in general detectors (whether DR or CR) performed satisfactorily. The chief limitation in performing these tests was that not all systems provided ready access to pixel values. Subjective tests include the use of the Leeds TO20. As part of this work, suggested reference values are provided to calculate the TO20 image quality factor. One consequence of moving from film screen to digital technologies is that the dynamic range of digital detectors is much wider, and increased exposures are no longer evident from changes in image quality. As such, AEC is a key parameter for CR and DR. Dose was measured using a standard phantom as a basic means of comparing systems. In order to assess the AEC performance, exit doses were also measured while varying phantom thickness. Signal-to-noise ratios (SNRs) were calculated on a number of systems where pixel values were available. SNR was affected by the selection of acquisition protocol. Comparisons between different technologies and collation of data will help refine acceptance thresholds and contribute to optimising dose and image quality.

A training syllabus for radiation protection in dental radiology.

The EU Council Directive 97/43/EURATOM (MED) states that Member States shall ensure that adequate theoretical and practical training is provided for dental practitioners working with ionising radiation; this also includes the provision of continuing education and training programmes, post-qualification. The area of dental radiology is specifically mentioned in this legally binding document. The Department of Medical Physics and Bioengineering, St James's Hospital, Dublin, is particularly interested in the area of radiation protection training and routinely provides educational courses both at national and international levels. A recent review of their dental radiation protection course was undertaken in conjunction with a number of Principal Dental Surgeons within the Health Service Executive in Ireland. The revised course was delivered to over 200 dental staff members at two separate meetings during 2006. The response from attendees was very positive. It is proposed to extend this course to other dental professionals, working both in the Irish private and public health sectors in the future.

European survey of dental X-ray equipment.

The implementation of an X-ray Quality Assurance (QA) program is a legal requirement in Europe as stipulated in the EU Council Directive 97/43/EURATOM (MED). A review of the literature has identified that European countries are performing some level of QA testing of their dental X-ray equipment, although the type and level to which testing is performed can differ. The European SENTINEL co-ordination action proposed to collate a survey of equipment data for both conventional and digital dental X-ray installations among the SENTINEL partners. The European QA results confirm that systems can be operated below tolerance, and in some cases significantly so, while still in clinical use. This can occur despite servicing of equipment. The results have emphasised the fact that there is a requirement for the medical physics/engineering professions to become more closely involved in the management of dental radiology equipment. This also includes their involvement in the development and delivery of appropriate training courses for dentists and suppliers of dental radiology equipment.

Acceptance testing of fluoroscopy systems used for interventional purposes.

This study presents the results of acceptance testing on 18 interventional fluoroscopy systems in Ireland. Acceptance testing and routine quality assurance (QA) of X-ray systems are the requirements of the EU Medical Exposures Directive (MED) and these requirements were subsequently implemented into Irish legislation. The MED states that special consideration should be given to the QA and dose assessment of high dose procedures such as interventional fluoroscopy. Owing to the advances in fluoroscopy technology, it has been found that comprehensive testing of interventional systems proves challenging in a busy hospital environment. A number of recurrent problems have been identified and are presented.

Acceptance testing and QA of interventional cardiology systems.

Interventional cardiology (IC) is a rapidly growing field of medical specialisation. Such procedures are complex and may subject patients and operators to higher levels of risk than those encountered in general radiology. Acceptance testing and quality assurance (QA) of radiological equipment, including IC equipment, is a requirement of the EU Medical Exposures Directive (MED) (97/43/EURATOM). In addition, the MED identifies interventional radiology as an area of special concern. This study presents the results of a survey of 17 IC systems (including several flat panel detector systems) in Irish hospitals. The results of the survey indicate large differences in patient doses between manufacturers for equivalent levels of measured image quality. In addition, all systems were found to have failed one or more acceptance tests, with 60% of systems demonstrating significant problems at acceptance testing. The results of the survey demonstrate the importance of acceptance testing and QA in IC. The results also provide baseline data, which may be used in the development of future QA guidelines.

QA/acceptance testing of DEXA X-ray systems used in bone mineral densitometry.

New developments in dual energy X-ray absorptiometry (DEXA) imaging technology [fan beam and cone beam (CB)] result in higher exposure levels, shorter scan times, increased patient throughput and increased shielding requirements. This study presents the results of a European survey detailing the number and location of DEXA systems in SENTINEL partner states and the QA (quality assurance) currently performed by physicists and operators in these centres. The results of a DEXA equipment survey based on an in-house developed QA protocol are presented. Measurements show that the total effective dose to the patient from a spine and dual femur DEXA examination on the latest generation DEXA systems is comparable with a few microSv at most. Scatter measurements showed that the use of a mobile lead screen for staff protection was necessary for fan and CB systems. Scattered dose from newer generation systems may also exceed the exposure limits for the general public so structural shielding may also be required. Considerable variation in the magnitude and annual repeatability of half value layer was noted between different models of DEXA scanners. A comparative study of BMD (bone mineral density) accuracy using the European Spine Phantom highlighted a deviation of up to 7% in BMD values between scanners of different manufacturers.

Reference levels at European level for cardiac interventional procedures.

In interventional cardiology, a wide variation in patient dose for the same type of procedure has been recognised by different studies. Variation is almost due to procedure complexity, equipment performance, procedure protocol and operator skill. The SENTINEL consortium has performed a survey in nine european centres collecting information on near 2000 procedures, and a new set of reference levels (RLs) for coronary angiography and angioplasty and diagnostic electrophysiology has been assessed for air kerma-area product: 45, 85 and 35 Gy cm2, effective dose: 8, 15 and 6 mSv, cumulative dose at interventional reference point: 650 and 1500 mGy, fluoroscopy time: 6.5, 15.5 and 21 min and cine frames: 700 and 1000 images, respectively. Because equipment performance and set-up are the factors contributing to patient dose variability, entrance surface air kerma for fluoroscopy, 13 mGy min(-1), and image acquisition, 0.10 mGy per frame, have also been proposed in the set of RLs.