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.

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.

First record of Pellonyssus gorgasi Yunker & Radovsky, 1966 (Mesostigmata: Macronyssidae) in Cuba and a new host association

The mite Pellonyssus gorgasi Yunker & Radovsky is recorded for the first time in Cuba, based on several specimens collected on a young Cuban Emerald, Riccordia ricordii ricordii (Gervais) (Apodiformes: Trochilidae) and in its nest from San Antonio de los Baños, Artemisa Province. In this study, R. r. ricordii represents a new host-association for P. gorgasi, whereas the genus Pellonyssus is also recorded for the first time in Cuba.

Mites (Mesostigmata: Melicharidae) associated with hummingbirds (Aves: Trochilidae) in Brazil

Mites of the family Melicharidae comprise 13 genera and 220 species often associated with edaphic environments and found in association with insects, birds and mammals. Two genera, Proctolaelaps and Tropicoseius, have been recorded in Brazil in association with birds and bromeliads. In this study, we add new locality and host-association records for Proctolaelaps superagui and Tropicoseius braziliensis in the country.

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.

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.

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.

Life beyond a diagnosis of glioblastoma: a systematic review of the literature.

BACKGROUND: The median survival of glioblastoma is 12-14 months with less than 10% of patients surviving at least 2 years from diagnosis. Patients diagnosed with glioblastoma face poor prognosis, significant symptom burden, and high care needs. The aim of this study is to undertake a literature review to document the issues encountered by long-term survivors of glioblastoma, a small but important subset of patients. METHODS: MEDLINE, PsychInfo, and EMBASE were searched with core concepts: (1) glioblastoma, (2) survivor, and (3) terms pertaining to survivorship issues. A thematic analysis was undertaken of the three included studies. RESULTS: Long-term survivors of glioblastoma encounter neurologic deficits, impairment in cognition, psychological distress, reduced social function, and future uncertainty. These issues result in the inability to return to work and financial difficulties. Independence in activities of daily living, working memory, and overall quality of life appears to be preserved. CONCLUSIONS: Long-term survivors of glioblastoma continue to have significant symptom burden and care needs. There is currently a paucity of literature surrounding this topic. Further research is required to accurately describe these issues in order for improved supportive care to be implemented in the community and the outpatient setting. IMPLICATIONS FOR CANCER SURVIVORS: Understanding the issues faced by long-term survivor of glioblastoma will provide insight into the care needs of patients as well as support networks required for patients and their carers.

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.

Occupational radiation dose to eyes from interventional radiology procedures in light of the new eye lens dose limit from the International Commission on Radiological Protection.

OBJECTIVE: In 2011, the International Commission on Radiological Protection (ICRP) recommended a substantial reduction in the equivalent dose limit for the lens of the eye, in line with a reduced threshold of absorbed dose for radiation-induced cataracts. This is of particular relevance in interventional radiology (IR) where it is well established that staff doses can be significant, however, there is a lack of data on IR eye doses in terms of Hp(3). Hp(3) is the personal dose equivalent at a depth of 3 mm in soft tissue and is used for measuring lens dose. We aimed to obtain a reliable estimate of eye dose to IR operators. METHODS: Lens doses were measured for four interventional radiologists over a 3-month period using dosemeters specifically designed to measure Hp(3). RESULTS: Based on their typical workloads, two of the four interventional radiologists would exceed the new ICRP dose limit with annual estimated doses of 31 and 45 mSv to their left eye. These results are for an "unprotected" eye, and for IR staff who routinely wear lead glasses, the dose beneath the glasses is likely to be significantly lower. Staff eye dose normalized to patient kerma-area product and eye dose per procedure have been included in the analysis. CONCLUSION: Eye doses to IR operators have been established using a dedicated Hp(3) dosemeter. Estimated annual doses have the potential to exceed the new ICRP limit. ADVANCES IN KNOWLEDGE: We have estimated lens dose to interventional radiologists in terms of Hp(3) for the first time in an Irish hospital setting.

High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.

Obesity is generally recognized as a condition which positively influences bone mass and bone mineral density (BMD). Positive effect of high body mass index (BMI) on bone has been recognized as a result of increased mechanical loading exerted on the skeleton. However, epidemiologic studies indicate that obesity is associated with increased incidence of fractures. The results presented here offer a new perspective regarding the mechanisms which may be responsible for the increase of bone mass and concurrent decrease in bone quality. Two groups of 12 week old C57BL/6 males were fed either high fat diet (HFD) or regular diet (RD) for 11 weeks. Metabolic profile, bone parameters and gene expression were assessed in these groups at the end of the experiment. Additionally, bone status was evaluated in a third group of 12 week old animals corresponding to animals at the start of the feeding period. Administration of HFD resulted in development of a diet-induced obesity (DIO), glucose intolerance, alteration in energy metabolism, and impairment in WAT function, as compared to the age-matched control animals fed RD. The expression of adiponectin, FABP4/aP2, DIO2 and FoxC2 were decreased in WAT of DIO animals, as well as transcript levels for IGFBP2, the cytokine regulating both energy metabolism and bone mass. At the end of experiment, DIO mice had higher bone mass than both control groups on RD, however they had decreased bone formation, as assessed by calcein labeling, and increased marrow adipocyte content. This study suggests that the bone mass acquired in obesity is a result of a two-phase process. First phase would consist of either beneficial effect of fat expansion to increase bone mass by increased mechanical loading and/or increased production of bone anabolic adipokines and/or nutritional effect of fatty acids. This is followed by a second phase characterized by decreased bone formation and bone turnover resulting from development of metabolic impairment.

Annexin A1 complex mediates oxytocin vesicle transport.

Oxytocin is a major neuropeptide that modulates the brain functions involved in social behaviour and interaction. Despite of the importance of oxytocin for the neural control of social behaviour, little is known about the molecular mechanism(s) by which oxytocin secretion in the brain is regulated. Pro-oxytocin is synthesised in the cell bodies of hypothalamic neurones in the supraoptic and paraventricular nuclei and processed to a 9-amino-acid mature form during post-Golgi transport to the secretion sites at the axon terminals and somatodendritic regions. Oxytocin secreted from the somatodendritic regions diffuses throughout the hypothalamus and its neighbouring brain regions. Some oxytocin-positive axons innervate and secrete oxytocin to the brain regions distal to the hypothalamus. Brain oxytocin binds to its receptors in the brain regions involved in social behaviour. Oxytocin is also secreted from the axon terminal at the posterior pituitary gland into the blood circulation. We have discovered a new molecular complex consisting of annexin A1 (ANXA1), A-kinase anchor protein 150 (AKAP150) and microtubule motor that controls the distribution of oxytocin vesicles between the axon and the cell body in a protein kinase A (PKA)- and protein kinase C (PKC)-sensitive manner. ANXA1 showed significant co-localisation with oxytocin vesicles. Activation of PKA enhanced the association of kinesin-2 with ANXA1, thus increasing the axon-localisation of oxytocin vesicles. Conversely, activation of PKC decreased the binding of kinesin-2 to ANXA1, thus attenuating the axon-localisation of oxytocin vesicles. The result of the present study suggest that ANXA1 complex coordinates the actions of PKA and PKC to control the distribution of oxytocin vesicles between the axon and the cell body.

Influence of S. mutans on base-metal dental casting alloy toxicity.

We have highlighted that exposure of base-metal dental casting alloys to the acidogenic bacterium Streptococcus mutans significantly increases cellular toxicity following exposure to immortalized human TR146 oral keratinocytes. With Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), S. mutans-treated nickel-based (Ni-based) and cobalt-chromium-based (Co-Cr-based) dental casting alloys were shown to leach elevated levels of metal ions compared with untreated dental casting alloys. We targeted several biological parameters: cell morphology, viable cell counts, cell metabolic activity, cell toxicity, and inflammatory cytokine expression. S. mutans-treated dental casting alloys disrupted cell morphology, elicited significantly decreased viable cell counts (p < 0.0001) and cell metabolic activity (p < 0.0001), and significantly increased cell toxicity (p < 0.0001) and inflammatory cytokine expression (p < 0.0001). S. mutans-treated Ni-based dental casting alloys induced elevated levels of cellular toxicity compared with S. mutans-treated Co-Cr-based dental casting alloys. While our findings indicated that the exacerbated release of metal ions from S. mutans-treated base-metal dental casting alloys was the likely result of the pH reduction during S. mutans growth, the exact nature of mechanisms leading to accelerated dissolution of alloy-discs is not yet fully understood. Given the predominance of S. mutans oral carriage and the exacerbated cytotoxicity observed in TR146 cells following exposure to S. mutans-treated base-metal dental casting alloys, the implications for the long-term stability of base-metal dental restorations in the oral cavity are a cause for concern.

Criteria and suspension levels in diagnostic radiology.

The EC (European Council) Directive on radiation protection of patients requires that criteria for acceptability of equipment in diagnostic radiology, nuclear medicine and radiotherapy be established throughout the member states. This study reviews the background to this requirement and to its implementation in practice. It notes and considers parallel requirements in the EC medical devices directive and International Electrotechnical Commission standards that it is also important to consider and that both sets of requirements should ideally be harmonised due to the global nature of the equipment industry. The study further reviews the types of criteria that can be well applied for the above purposes, and defines qualitative criteria and suspension levels suitable for application. Both are defined and relationships with other acceptance processes are considered (including acceptance testing at the time of purchase, commissioning and the issue of second-hand equipment). Suspension levels are divided into four types, A, B, C and D, depending on the quality of evidence and consensus they are based on. Exceptional situations involving, for example, new or rapidly evolving technology are also considered. The publication and paper focuses on the role of the holder of the equipment and related staff, particularly the medical physics expert and the practitioner. Advice on how the criteria should be created and implemented is provided for these groups and how this might be coordinated with the supplier. Additional advice on the role of the regulator is provided.

Doses measured using AEC on direct digital radiographic (DDR) X-rays systems: updated results with an RP 162 perspective.

As digital technology in diagnostic radiology systems becomes more prevalent, there is a need to provide comparative dose information for these new systems. This is needed in particular for testing the automatic exposure control (AEC) devices on direct digital radiography (DDR) systems as there is no consensus on the receptor dose level in the current guidelines. The new European Commission RP 162 document sets the suspension level for the 'verification of kerma at receptor entrance in computed radiography and DDR systems under AEC' as ≥10 µGy. This document also notes that alternate methodologies are acceptable, and may require adjustment in the suspension level if used. This study provides a range of typical doses under AEC for DDR systems, for a variety measurement methodologies, including that described in RP 162.

Practical application of suspension criteria scenarios in general radiography, computed radiography,digital radiography and fluoroscopy.

Radiological equipment must be assessed against criteria for acceptability to ensure that it meets the minimum standards for patient safety. This assessment is typically led by a medical physicist with input from radiology staff and the equipment supplier. Equipment that does not meet the criteria requires action and may be suspended from clinical use. European Commission report RP 91 will be revised and replaced as RP 162. It has been drawn up to aid medical physicists with the assessment process and provide guidance on suspension levels. This paper details several cases where the criteria in the proposed RP 162 were applied in general radiography, computed radiography, digital radiography and fluoroscopy. The factors considered by the medical physicist and the outcome of each case are presented. The proposed RP 162 report improves on its predecessor and provides a robust set of criteria for ensuring that patient safety within the EU medical exposures framework is optimised.

Application of European suspension criteria to dental radiology: an Irish perspective.

The European Medical Exposures Directive 97/43/Euratom aims to ensure that measures are put in place to guarantee that X-ray equipment is suitable for clinical use. The Directive was transposed into Irish legislation in Statutory Instruments 478 of 2002 and 2010. This study presents the quality assurance (QA) assessment results for 187 intra-oral and 37 orthopantomogram (OPG) dental X-ray systems from a range of nine different manufacturers. The equipment was assessed over a 24- month period. Testing was performed based on the methodologies and tolerances from Irish and other international guidelines and standards.  Analysis of the results which was undertaken in recent months with a focus on the suspension tolerances proposed in the Criteria for Acceptability of Medical Radiological Equipment (RP 162) are presented in this paper.

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.