bluuebunny/crossref_metadata_2025 huggingface dataset:
General versus Regional Anesthesia and Neonatal Data: A Propensity-Score-Matched Study
Authors: Cojocaru Liviu , Salvatori Cristiana , Sharon Amir , Seung Hyunuk , Nyman Katherine , Kodali Bhavani S. , Turan Ozhan M.
Published: October 2022

Objective This study aimed to evaluate whether there is a difference in neonatal outcomes with general anesthesia (GA) versus regional anesthesia (RA) when induction of anesthesia to delivery time (IADT) is prolonged (≥10 minutes).

Study Design This is a retrospective case–control study that included cases from July 2014 until August 2020. We reviewed all singleton pregnancies delivered between 24 and 42 weeks of gestation with IADT ≥ 10 minutes. Urgent deliveries, those who received RA for labor pain management or started cesarean delivery under RA and converted to GA, as well as cases with fetal anomalies, were excluded. The propensity score (PS) matching method was performed using age, ethnicity/race, body mass index, gestational age at delivery, preexisting maternal comorbidities, and pregnancy complications. Analyses were performed with SAS software version 9.4.

Results During the study period, we identified 258 cases meeting inclusion criteria. After the PS matching was applied, the study sample was reduced to 60 cases in each group. The median IADT and uterine incision to delivery time were similar between groups (41.5 [30.5, 52] vs. 46 minutes [38, 53.5], p = 0.2 and 1.5 [1, 3] vs. 2 minutes [1, 3], respectively). There was no significant difference between groups with respect to arterial or venous cord pH (7.24 [7.21, 7.26] vs. 7.23 [7.2, 7.27], p = 0.7 and 7.29 [7.26, 7.33] vs. 7.3 [7.26, 7.33], p = 0.4, respectively). Nor were there any associations between maternal characteristics and Apgar's score at 5 minutes, except for Apgar's score at 1 minute (p < 0.001). No significant difference was identified in the rate of admission to the neonatal intensive care unit (NICU; 11 [52.4%] vs. 10 [47.6%], p = 0.8) or NICU length of stay between GA and RA (4 [3, 14] vs. 4.5 [3, 11], p = 0.9).

Conclusion Our data indicate that even with prolonged IADT, favorable neonatal outcomes are seen with both GA and RA, in contrast with previous studies performed decades ago.

Key Points
Dynamics of homogeneous cavitation with pressure feedback
Authors: Zhang Xuewei , Li Jing , Shneider Mikhail N.
Published: October 2022

Theoretical studies of homogeneous cavitation have largely been based on the classical nucleation theory. However, existing cavitation models cannot adequately describe its dynamics at nanosecond timescale, which has been called for in other fields. We develop a model coupling nucleation kinetics with cavity growth and pressure feedback as saturation mechanisms. Our numerical studies reveal the exponential dependence of cavitation characteristics such as saturation cavity density and most probable cavity radius on model parameters: Tolman length and initial pressure. This work also sheds light on the possibility of accurately determining Tolman length, whose value has a large spread in the literature.
Turbines and motors made of DNA
Authors: Miller Johanna L.
Published: October 2022

The medium of life’s genetic code is also a versatile structural material for building nanoscale machines.
Social Frailty in Late Adulthood: Social Cognitive and Psychological Well-Being Correlates
Authors: Henry Julie D , Coundouris Sarah P , Mead Jessica , Thompson Brielle , Hubbard Ruth E , Grainger Sarah A
Published: October 2022

Objectives

Social frailty poses a major threat to successful aging, but its social cognitive and psychological well-being correlates remain poorly understood. This cross-sectional study provides initial insights into whether social cognitive difficulties in older age are associated with social frailty, as well as how social frailty is linked to psychological characteristics known to be important for health and well-being.

Method

Ninety community-dwelling older adults completed measures of social frailty and social cognition (social perception, theory of mind, affective empathy, and informant-rated social behavior) as well as measures of psychological function known to be important for health and well-being, both positively (resilience and life satisfaction) and negatively (demoralization, social anxiety, and apathy). Measures of cognitive frailty, physical frailty, and depression were also administered to test the specificity of any observed relationships with social frailty.

Results

Both affective empathy and social behavior were predictive of increased social frailty, but social behavior emerged as the only unique predictor after controlling for covariates. Social frailty also predicted unique variance in all five measures of psychological well-being, and for three of these measures (demoralization, resilience, and life satisfaction), the effects remained significant even after adjusting for covariates.

Discussion

Findings are discussed in relation to models of socioemotional aging and frailty. Potential mechanisms linking social behavior to social capital in older age are identified, as well as how loss of social resources might both directly and indirectly impact well-being.
Receptive Language Abilities for Females Exposed to Early Life Adversity: Modification by Epigenetic Age Acceleration at Midlife in a 30-Year Prospective Cohort Study
Authors: Felt John M , Harrington Karra D , Ram Nilam , O’Donnell Kieran J , Sliwinski Martin J , Benson Lizbeth , Zhang Zhenyu , Meaney Michael J , Putnam Frank W , Noll Jennie G , Shenk Chad E
Published: October 2022

Objectives

Deviations from normative trajectories of receptive language abilities following early life adversity (ELA) may indicate an elevated risk for advanced cognitive aging and related morbidities. Accelerated epigenetic aging at midlife may further identify those at greatest risk for advanced cognitive aging following ELA. We examined whether accelerations in epigenetic aging at midlife can identify those individuals who demonstrated the greatest change in receptive language abilities following ELA.

Methods

Data were drawn from the Female Growth and Development Study (n = 86), a 30-year prospective cohort study of females exposed to substantiated child sexual abuse (CSA), a severe ELA, and a non-CSA comparison condition. The Peabody Picture Vocabulary Test-Revised (PPVT-R) measured receptive language abilities on 6 occasions from childhood to mid-life. Interindividual differences in PPVT-R trajectories were examined in relation to CSA exposure and across 5 independent measures of epigenetic age acceleration derived from first (Horvath DNAmAge, Hannum DNAmAge) and second (GrimAge, PhenoAge, Dunedin Pace of Aging) generation epigenetic clocks.

Results

Quadratic growth models revealed that PPVT-R scores were significantly lower at age 25 for females exposed to CSA. Specifically, CSA exposed females had lower intercepts when GrimAge was accelerated and a smaller quadratic trend when PhenoAge was accelerated. 

Discussion

ELA is associated with significant differences in development of receptive language abilities with the most pronounced differences observed for females with accelerated epigenetic ages at mid-life. These findings suggest that epigenetic age acceleration could serve as an indicator of differences in cognitive aging and portend to later adulthood cognitive functioning.
Musical Exdurantism
Authors: Letts Philip
Published: October 2022

Recently, Caterina Moruzzi has appealed to Ted Sider’s case for continuant exdurantism and the availability of a “parallel move” in musical ontology to promote a specific version of musical work exdurantism. In this article, I argue that her version of musical exdurantism undermines the prospects for making the parallel move, but I go on to sketch two alternatives that do not. In Section I, I outline apparent persistence-parallels between ordinary material objects and musical works. In Section II, I sketch a transposable case for accepting continuant exdurantism. In Section III, I introduce Moruzzi’s exdurantism. In Section IV, I introduce her selected rivals—the type-token theory of Julian Dodd and an austere musical perdurantism due to Ben Caplan and Carl Matheson. In Section V, I argue that several of Moruzzi’s commitments undermine her motivation from the “parallel move.” In sections VI and VII, I sketch alternative versions of musical exdurantism that are better positioned to adopt the parallel move.
Effect of live yeast supplementation on energy partitioning and ruminal fermentation characteristics of steers fed a grower-type diet in heat-stress conditions
Authors: D’Souza Genevieve M , Dias Batista Luiz Fernando , Norris Aaron B , Tedeschi Luis O
Published: October 2022

The objective of this trial was to determine the influence of live yeast supplementation (LY), environmental condition (ENV), and their interaction (TRT) on energy partitioning, nitrogen metabolism, and ruminal fermentation dynamics of steers receiving a grower-type diet. The effects of LY and ENV were investigated using a 2 × 2 crossover design that spanned five periods. Eight Angus-crossbred steers were randomly split into pairs and housed in four outdoor pens outfitted with an individualized feeding system. Animals were limit-fed a grower diet (DIET) at 1.2% shrunk body weight (SBW) with no live yeast supplementation (NOY) or a grower diet top-dressed with 10 g LY/d for 14 d (1.2 × 1012 CFU/d). On days 13 and 14, animals were subjected to one of two ENV conditions, thermoneutral (TN; 18.4 ± 1.1 °C, 57.6 ± 2.8% relative humidity [RH]) or heat stress (HS; 33.8 ± 0.6 °C, 55.7 ± 2.7% RH), in two side-by-side, single-stall open-circuit, indirect respiration calorimetry chambers. Data were analyzed using a random coefficients model. Carryover effects were examined and removed from the model if not significant. Gross (GE), digestible, metabolizable, heat, and retained energies were not influenced by DIET, ENV, or TRT (P ≥ 0.202). Gaseous energy, as a percentage of GE, tended to increase during HS (P = 0.097). The only carryover effect in the study was for oxygen consumption (P = 0.031), which could be attributed to the tendency of NOY (P = 0.068) to have greater oxygen consumption. DIET, ENV, or TRT (P ≥ 0.154) had no effects on total animal methane or carbon dioxide emissions. Similarly, DIET, ENV, or TRT (P ≥ 0.157) did not affect ruminal pH, redox, protozoa enumeration, ruminal ammonia concentrations, and acetate-to-propionate ratio. Propionate concentrations were the greatest in animals in TN conditions receiving LY (P = 0.034) compared to the other TRT. This effect is mirrored by TN-LY tending to have greater acetate concentrations (P = 0.076) and total VFA concentrations (P = 0.065). Butyrate concentrations tended to be greater for animals fed LY (P = 0.09). There was a tendency for LY to have elevated numbers of Fusobacterium necrophorum (P = 0.053). Although this study lacked effects of LY on energy partitioning, nitrogen metabolism, and some ruminal parameters during HS, further research should be completed to understand if LY is a plausible mitigation technique to enhance beef animals’ performance in tropical and sub-tropical regions of the world.
Alginate Dressings Continuously for 14 Days on Uncontaminated, Superficial, Partial Thickness Burns
Authors: Stynes Gil , Haertsch Peter , O’Hara Justine , Knight Robert , Issler-Fisher Andrea C , Maitz Peter K M
Published: October 2022

Calcium alginate dressings are commonly used on split-thickness skin donor sites, where they are typically removed after 14 days. Alginates have been used previously on superficial, partial thickness burns, but changed every 3 to 5 days. In this study, alginates were applied to superficial, partial thickness burns on adults within 36 hours of injury, then left intact for up to 14 days. Wound healing (≥95% wound epithelialization) and pain were measured. Twenty-one burns were reviewed on ten patients. Per the initial protocol, six patients were reviewed every 3 to 5 days, with removal of only secondary dressings, until days 13 to 14, when the alginate dressings were removed. One patient was reviewed every 3 to 5 days until day 10, when a clinic nurse removed the alginate dressing. Restrictions on movement during the COVID pandemic necessitated a protocol change, with only one review at approximately day 14 for removal of alginate and secondary dressings; three patients were reviewed in this manner. Burns on all patients were 100% epithelialized at the time of final review and there were no complications, such as scarring, infection, or need for grafting. Following initial debridement and dressings, patients reported minimal pain. Dressing costs appeared to be significantly decreased. This protocol may be particularly useful for patients managed in rural and remote locations, with telemedicine support if required.
Outcomes of COPD Patients with Flame Burn and Inhalation Injuries at a Single Institution
Authors: Nam Jason , Sljivic Sanja , Matthews Robert , Pak Joyce , Agala Chris B , Nizamani Rabia , King Booker , Williams Felicia N
Published: October 2022

The presence of any comorbid condition may lead to worse outcomes after burn injury. Chronic obstructive pulmonary disease (COPD) is a condition with significant morbidity and mortality. In 2018, about 16 million adults in the United States reported a diagnosis of COPD based on data from the American Lung Association. The objective of this study was to explore the outcomes of patients with COPD admitted to our Burn Center with flame burns and/or inhalation injury. Patients were identified using our Institutional Burn Center registry and linked to the clinical and administrative data. All adult flame-injured and/or inhalation injury-only patients admitted to our burn center between July 1, 2011 and June 30, 2020 were included. Demographics, length of stay, burn, and patient characteristics and outcomes, including mortality, were evaluated. Four thousand three hundred ninety-seven patients were included in the study. Patients were divided into two populations, those with COPD (n = 515) and those without a diagnosis of COPD (n = 3882). Patients with COPD were older, more likely to be white and male, and had smaller sized burns, p < .001. Patients with COPD were more likely to be smokers and have comorbid conditions. There was no statistically significant difference between the incidence of inhalation injury, lengths of stay, or number of ventilator days. Burn size and inhalation injury increased mortality risk regardless of COPD severity, as did age among those not on home oxygen. More studies are needed to determine the genomic or proteomic changes in patients with COPD that lead to worse outcomes after flame injury, and/or inhalation injury alone.
Azithromycin concentration in rabbits’ plasma and posterior segment of the eyes following oral drug administration: a dose-finding study for the application in ocular toxoplasmosis
Authors: Daniel Hisar , Louisa Melva , Edwar Lukman
Published: October 2022

Introduction

Azithromycin has been used as an ocular toxoplasmosis alternative treatment due to its pharmacokinetic profiles. However, sufficient concentrations to promote toxoplasmosis eradication is still unknown. This study was aimed to evaluate azithromycin levels in rabbits after three regimens equivalent to human doses for ocular toxoplasmosis.

Methods

Three groups of New Zealand albino rabbits were given one of the following: azithromycin at 26 mg/kg BW daily (Group 1), 26 mg/kg BW every two days (Group 2), and 50 mg/kg BW once weekly (Group 3) for 14 days. Plasma and ocular azithromycin concentrations were examined.

Results

Following 14 days, median ratio of plasma maximum azithromycin concentration to the minimum inhibitory concentration for Toxoplasma gondii (C-max/MIC) for Group 1, and 2 were 51.29, 5.33, while Group 3 was undetected. The median azithromycin concentration in the retina-choroid was higher than the MIC in Group 1 (1356.0 ng/ml) and Group 2 (189.0 ng/ml), but not in Group 3.

Conclusion

Azithromycin administered orally at the dose of 26 mg/kg BW daily or 26 mg/kg BW every two days resulted a sufficient criteria of C-max/MIC as well as retina-choroid concentration needed for its parasiticidal activity. However, well-conducted clinical trial is warranted to support its therapeutic potential in ocular toxoplasmosis.
Primary cavernous hemangioma of the thyroid mimicking an ectopic cervical thymoma
Authors: Díaz-García Alberto , Caballero-Rodríguez Eugenia , García-Martínez Rubén , Balanzá Julio Jordán , Gómez Manuel Ángel Barrera
Published: October 2022

Hemangiomas are one of the most common soft tissue tumors, most of which are located in the skin and subcutaneous tissue. However, a primary thyroid hemangioma is extremely infrequent, so there are only a few cases described in the current literature. As the clinical presentation and characteristics in the imaging tests are non-specific, it is difficult to obtain a preoperative diagnosis. In most cases, the definitive diagnosis is achieved by the histological examination. Due to the rarity of this tumor, we described the case of a 51-year-old female patient affected by thyroid cavernous hemangioma, the differential diagnosis that we considered and a review of the current literature.
Visual binary stars with known orbits in Gaia EDR3
Authors: Chulkov Dmitry , Malkov Oleg
Published: October 2022

A total of 3350 objects from the Sixth Catalog of Orbits of Visual Binary Stars (ORB6) are investigated to validate Gaia Early Data Release 3 (EDR3) parallaxes and provide mass estimates for the systems. We show that two-thirds of binaries with a separation of 0.2–0.5 arcsec are left without a parallax solution in EDR3. Special attention is paid to 521 pairs with the parallax known separately for each component. We find 16 entries that are deemed to be chance alignments of unrelated stars. First we show examples of high-confidence binary systems with significant differences in the reported parallaxes of their components. Next we conclude that the reported Gaia EDR3 parallax errors are underestimated, by at least a factor of 3, for sources with a large renormalized unit-weight error (RUWE). Parallaxes are needed to estimate stellar masses. Because nearly 30 per cent of ORB6 entries lack a 5- or 6-parameter solution in EDR3, we attempt to enrich the astrometric data. Distant companions of ORB6 entries are revealed in EDR3 by the analysis of stellar proper motions and Hipparcos parallaxes. Notably, in 28 cases, intrinsic EDR3 parallaxes of the binary components appear to be less reliable than the parallax of the outer companions. Gaia DR2, The Tycho-Gaia Astrometric Solution (TGAS) and Hipparcos parallaxes are used when EDR3 data are unavailable. A synthetic mass–luminosity relationship in the G band for main-sequence stars is obtained to provide mass estimates along with dynamical masses calculated via Kepler’s third law.
sstar: A Python Package for Detecting Archaic Introgression from Population Genetic Data with S*
Authors: Huang Xin , Kruisz Patricia , Kuhlwilm Martin
Published: October 2022

S* is a widely used statistic for detecting archaic admixture from population genetic data. Previous studies used freezing-archer to apply S*, which is only directly applicable to the specific case of Neanderthal and Denisovan introgression in Papuans. Here, we implemented sstar for a more general purpose. Compared with several tools, including SPrime, SkovHMM, and ArchaicSeeker2.0, for detecting introgressed fragments with simulations, our results suggest that sstar is robust to differences in demographic models, including ghost introgression and two-source introgression. We believe sstar will be a useful tool for detecting introgressed fragments in various scenarios and in non-human species.
Pro-drug Nanoparticle Loaded Supramolecular Hydrogels for Drug Delivery to IDH1 Wild-Type Glioblastoma
Authors: Cavanagh Robert , Baquain Saif , Alexander Cameron , Scherman Oren , Rahman Ruman
Published: October 2022

AIMS

A hyaluronic acid-based hydrogel with mechanical properties comparable to human brain tissue is being investigated as an implantable drug-delivery vehicle for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). Hydrogels are to be loaded with polymeric pro-drug nanoparticles to enable controlled drug release and increased drug penetration through brain parenchyma for enhanced treatment of residual disease within and beyond the invasive margin.

METHOD

A panel of patient-derived glioblastoma cell lines resected from tumour core and invasive margin, have been used to generate tumour spheroids. Chemotherapeutic drug screening has been performed to select lead compounds for formulation and gel loading. Synergies of drug combinations have been studied for potential combination loading. Upcoming work will investigate nanoparticle internalisation, spheroid penetration and prodrug nanoparticle potency. Nanoparticle loaded hydrogels are then to be studied for validation of effective in vitro application.

RESULTS

Current results demonstrate that patient-derived cell lines can generate robust, reproducible tumour spheroids with diameters approx. 350-400 µm. Patient-to-patient differences in drug potencies were observed, with differences also noted between counterpart core and marginal cells from the same patients, illustrating the importance of using patient-derived cells and distinct regional cells to study heterogenous disease such as GBM. Drug combination experiments indicated synergy of topoisomerase I inhibitor (Irinotecan) with PARP inhibitor (Ola-parib). Interestingly, combination of PARP inhibition with topoisomerase II inhibitors (Doxorubicin, Etoposide) was found not synergistic.

CONCLUSION

Together, data gathered on single drug and drug-drug combinations will inform upcoming formulation and in vitro application of hydrogels planned, with eventual translation to pre-clinical in vivo models.
Modelling SHH-Medulloblastoma Using Cerebellar Organoids
Authors: van Essen Max , Kilfeather Peter , Cowley Sally , Jacob John , Becker Esther
Published: October 2022

AIMS

Medulloblastoma (MB) comprises four main groups (SHH, WNT, group 3 and group 4), with distinct molecular, clinical and demographic features. These differences suggest opportunities for tailored and improved treatment. Despite its promise, translation into targeted therapy has been slow, limited by the lack of laboratory models that recapitulate patient tumours. Sporadic and inherited forms of SHH-MB are frequently due to mutations in the tumour suppressor gene PTCH1. Here, we aim to exploit human induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 gene editing, to target PTCH1 in a clinically relevant context, thereby establishing an innovative model of MB.

METHOD

CRISPR/Cas9 mutation of PTCH1 in hiPSCs was followed by their differentiation into cerebellar organoids. Mutant organoids were studied for early consequences on cerebellar development and tumorigenesis.

RESULTS

PTCH1-mutation resulted in enhanced SHH-pathway activity in cerebellar organoids. Homozygous PTCH1-mutation prevented the formation of cerebellar progenitor cells, closely mimicking the effects of high SHH- signalling on neuronal progenitors in early embryonal development. Heterozygous PTCH1-mutant hiPSCs could be differentiated into cerebellar organoids, displayed increased growth rate and expressed oncogenes specific to SHH-MB, resembling preneoplasia and MB stem cells.

CONCLUSION

These results show that cerebellar organoids are a promising new model to study early oncogenic events in MB. Our model presents opportunities for the discovery of new targets which could benefit patients with a genetic predisposition to MB in particular. Refined knowledge of early drivers will be invaluable to guide drug selection and improve prospects for clinical translation.
Hippocampal Dosimetry and Neurocognitive Function in Patients Undergoing Stereotactic Radiosurgery for Brain Metastases
Authors: Iqbal Sahar , Williams Maeve , Smalley Michelle , Daisley-Devoy Tara , Wise Richard , Staffurth John , Maclean Jillian , Tilsley Owen , Powell James
Published: October 2022

AIMS

To measure neurocognitive function (NCF) and correlate with hippocampus dose in patients undergoing stereotactic radiosurgery (SRS) for 1-3 brain metastases.

METHOD

We conducted a prospective observational study measuring NCF before and after SRS in patients with 1-3 brain metastases and correlated changes with hippocampal dosimetry Patients underwent NCF testing at baseline, 1 month, 3 months and 6 months post SRS and quality of life was measured at each time point. NCF tests included Hopkin’s Verbal learning test, controlled oral word association test and trail making tests. Hippocampus was outlined in line with RTOG guidance and dose was collected from the treatment planning system.

RESULTS

36 patients were recruited. Mean age was 64 years, median WHO performance status 1 (range 0-2). At baseline, 65% of patients displayed NCF impairment in at least 1 NCF domain and 33% didn’t exhibit any neurological symptoms. Asymptomatic patients has underlying diagnosis of non-small cell lung cancer or melanoma. NCF impairment was evident at 1, 3 and 6 months for 50%, 66% and 40% patients respectively. Decline at 1 month was associated with higher median dose to 0.1cc of hippocampus (5 Gy vs 2.35 Gy). Association with hippocampal dose and NCF impairment at 3 and 6 months was not observed.

CONCLUSION

A significant proportion of patients exhibited impaired NCF at baseline with greatest NCF decline seen at 1 months and subsequent recovery of NCF evident at 6 months. Dose to hippocampus 0.1cc may be associated with acute NCF toxicity. Main limitations of this study was small number of patients.
Glioma Cell Invasion Is Dependent Upon the DNA Damage Response Kinase ATR
Authors: Birch Joanna , Strathdee Karen , Derby Sarah , Koessinger Anna , Chalmers Anthony , Norman Jim , Carruthers Ross
Published: October 2022

AIMS

Gliomas have high levels of DNA replication stress and clinical trials of inhibitors of the key replication stress response protein ATR (ataxia telangiectasia and rad 3 related protein) as radiosensitisers are planned. We aimed to investigate the effect of ATR inhibition on the ability of glioma cells to infiltrate and invade the brain.

METHOD

Live cell imaging in a panel of primary glioma cultures following siRNA or pharmacological inhibition of ATR. Invasion following treatment of murine orthotopic gliomas was determined by immunohistochemistry. Intravital imaging of GFP expressing murine orthotopic xenografts via an intracranial window model of glioma was undertaken.

RESULTS

Invading margins of human glioma samples demonstrated increased pATR expression relative to core. Live cell imaging demonstrated reduced cell velocity following ATR inhibition (Berzosertib/BAY1895344) or siRNA. Cytoplasmic vacuolation occurred following ATRi or siRNA which were single walled structures which engulf high molecular weight dextran, compatible with blockade of macropinosome processing. Live cell imaging with GFP-integrin α5 and integrin recycling assays showed sequestration of integrins within macropinosomes and reduced integrin cycling. Intravital in vivo imaging of murine xenograft tumours confirmed vacuolation and dextran uptake following ATRi, whilst a further in vivo study demonstrated a reduction in invading tumour cells.

CONCLUSION

We demonstrate a novel role for ATR in facilitating macropinocytic vesicle trafficking and integrin recycling in GBM cells which results in a profound motility defect in vitro and in vivo. ATR inhibitors are entering early phase trials as radiation sensitisers and we propose that therapeutic benefit will extend beyond DNA damage potentiation.
Core outcomes in Brain Tumour Trials – The COBra Study Review of Glioma Trial Registration Data
Authors: Retzer Ameeta , Baddeley Elin , Sivell Stephanie , Seddon Kathy , Bulbeck Helen , Nelson Annmarie , Calvert Melanie , Grant Robin , Adams Richard , Watts Colin , Aiyegbusi Olalekan Lee , Rivera Samantha Cruz , Kearns Pamela , Dirven Linda , Byrne Anthony
Published: October 2022

AIMS

Trial registration supports unbiased reporting of research studies. Despite inconsistent use globally and sub-optimal completeness, registration is associated with publication of the same outcomes as defined in trial protocols, though these are not necessarily reported in published results. In the core outcomes in brain tumour trials (COBra) study a registry review was undertaken, alongside a systematic review of qualitative literature and semi-structured interviews, to develop a core outcome set (COS) outcome longlist. The study aims to identify all outcomes reported across all glioma trial registration data.

METHOD

Phase 3 interventional glioma trials involving patients aged 18 and over, registered on clinicaltrials.gov or the ISRCTN registry were included. Two researchers independently searched the databases and registered data and available protocols were retrieved. Two reviewers independently extracted basic trial data including primary and secondary outcomes. Outcomes were categorised according to an ontology developed through literature review.

RESULTS

91 trials were identified. Primary outcome categories reported were survival (84%), disease activity (14%), symptoms (4%), adverse events (3%) and resource use (1%). Secondary outcome categories reported were survival (60%), adverse events (52%), quality of life (QoL, 41%), disease activity (30%), symptoms (20%), function (12%), resource use (7%), health status (7%), and economic (3%). The review contributed 15 unique outcomes to the final outcome longlist of 35.

CONCLUSION

Trial registries represent a pragmatic solution in COS development and enabled identification of outcomes not present in other data sources. Under half of registered glioma studies included QoL outcomes; a small minority included functional outcomes or economic evaluation.
CaPaBLE - Assessing the Patient Generated Index Methodology in High Grade Glioma Patients and Caregivers
Authors: Pakzad-Shahabi Lillie , Tallant James , Le Calvez Kerlann , Wells Mary , Williams Matt
Published: October 2022

AIMS

CaPaBLE tests the feasibility and acceptability of assessing quality of life (QoL) using the patient-, or caregiver-generated index (PGI/CaGI) methodology in patients with HGG and their caregivers.

METHOD

CaPaBLE, (https://www.isrctn.com/ISRCTN45555598), followed patients and/or their caregivers up to 6 months. Standard measures for patients were EORTC QLQ-C30/BN20, for caregivers the CarGOQOL questionnaire. The QoL topics raised through PGI/CaGI have been coded to the most relevant domain from their respective standard measure for an initial assessment of concordance.

RESULTS

36 patients, 24 caregivers recruited to study; completing an average of 3 study assessment timepoints. PGI and CaGI generated 240 and 160 topics respectively. Patient concerns most frequently coded to EORTC domain of Role Functioning; Caregiver concerns mostly coded to CarGOQOL domain of Burden. Other topics frequently raised by patients such as the driving and sex life, and future planning by caregivers are not specifically raised in standard questionnaires.

CONCLUSION

Nearly all topics raised by patients and caregivers were mapped to the domains of their respective standard QoL measure. However, almost half of all topics raised by patients and caregivers mapped to a minority of the domains included in standard measures; whilst a notable number of topics are not specifically included in standard measures at all. This raises questions regarding the efficiency and relevance of such questionnaires to patient and caregivers’ daily lives.
The Anisotropic Component of the Diffusion Tensor (DTI-Q) Is Correlated to Overall Survival in Glioblastoma (GBM)
Authors: Simon Natalie , Sinha Rohit , Sravanam Sanskrithi , Mayrand Roxanne , Li Chao , Wan Yizhou , Wei Yiran , Price Stephen
Published: October 2022

AIMS

The aim of this study was to test if a correlation exists between the median voxel DTI-Q and overall survival in patients with GBM.

METHOD

The median voxel anisotropic (DTI-Q) values, calculated for the whole brain, the contrast-enhancing hemisphere and the contralateral hemisphere, were calculated using FSL (FMRIB Software Library, Oxford) for 33 patients with a primary diagnosis of GBM. Overall survival was calculated by subtracting the date of initial resection surgery from the date of death, for each included patient. Using R statistical software, the Pearson’s correlation coefficient was computed to establish the significance of the relationship between overall survival and whole brain median DTI-Q values, contrast-enhancing hemisphere median DTI-Q values and non-contrast-enhancing hemisphere median DTI-Q values.

RESULTS

There is a significant correlation between the median voxel DTI-Q of the whole brain and overall survival (t = -2.5362, df = 31, p-value = 0.01646), median voxel DTI-Q of the contrast-enhancing hemisphere and overall survival (t = -2.1235, df = 31, p-value = 0.0418) and the median voxel DTI-Q of the contralateral (non-contrast-enhancing) hemisphere and overall survival (t = -2.5212, df = 31, p-value = 0.01705).

CONCLUSION

The median anisotropic component of the diffusion tensor, calculated for the whole brain, contrast-enhancing and non-contrast-enhancing hemisphere, is significantly related to overall survival. This demonstrates the potential utility of DTI metrics as prognostic biomarkers that can readily be calculated in routine practice.
Low Grade Glioma - A COVID Low Surgical Priority?
Authors: White William , Rudd George , Zaki Hesham , McKevitt Fiona , Romanowski Charles , Ushewokunze Shungu
Published: October 2022

AIMS

During the COVID pandemic (March 2020) SBNS published guidance advising that low grade gliomas (LGG) should be categorised as “low surgical priority”, therefore surgery could be delayed by six months. Aims: (1) Examine the effect of the COVID pandemic on the time taken from neuro-oncology MDT discussion to surgery in presumed LGG. (2) Investigate the proportion of presumed LGG receiving an integrated diagnosis of high grade glioma (HGG) before and during the COVID pandemic.

METHOD

Retrospective case note analysis of patients with presumed LGG including radiological and histopathological reports. Population split into two groups – Group A pre-pandemic (March 2019-2020) and Group B mid-pandemic (March-December 2020).

RESULTS

Forty-three patients (30M, 13F) with presumed LGG were identified – 23/43 in Group A and 20/43 in Group B. Mean age was 45 years (26-77y). Twenty-two patients (Group A 12/23 (52%) & Group B 10/20 (50%)) had no radiological features of transformation. Mean number of days between discussion and surgery was 32 (2-96 days, SD=28) for group A and 98 (6-286 days, SD=92) for group B (p=.006: [95% CI: 21-110]). Fifteen patients in each group (65% v 75%) had an integrated diagnosis of HGG (p=.486). Of the patients with no radiological features of transformation 6 (50%) had a HGG in Group A and 7 (70%) in Group B (p=.342).

CONCLUSION

During the COVID pandemic patients with presumed LGG had their surgical management significantly delayed, with an increase in the proportion who were diagnosed with HGG. Presumed LGG patients should have higher surgical priority even when resources are constrained.
Seizure Semiology Over Time in Adult Diffuse Glioma
Authors: Carstairs Claire , Pandey Anmol , Moulder Zachary , Kosela Monika , Rees Jeremy
Published: October 2022

AIMS

Patients with gliomas often present with generalised seizures, but subsequently develop focal seizures on treatment. The occurrence of a single generalised seizure at onset precludes the return of a driving licence, even if a patient continues to have only focal aware seizures. We investigated seizure semiology over time, to determine how many patients with ongoing seizures may be safe to drive.

METHOD

We analysed clinical data of patients with histologically-confirmed IDH-mutant diffuse gliomas, diagnosed between 2004-2015. Seizures were classified as: 1 – focal / 2 - generalised; A – aware / B – unaware; M – motor / N – non-motor. Seizure type at diagnosis and last follow-up was recorded.

RESULTS

189 patients were identified, of whom 140 presented with seizures (74%). 115 of these patients had a full data set. 59 (51%) presented with generalised seizures. 10% had only a single seizure at presentation, 55 % had further seizures then became seizure-free and 35% continued to have seizures at last follow-up. Of the 40 patients who continued to have seizures, 7 (17.5%) had 1AN, 16 (40%) had 1AM, 1 (2.5%) had 1BN and 5 (12.5%) had 1BM. 11 (27.5%) had generalised seizures. Of the 7 patients with 1AN seizures at last follow-up, 4 initially presented with a generalised seizure, 1 with 1AN, 1 with 1AM and 1 with 1BM.

CONCLUSION

Almost two thirds of patients became seizure-free and, of those that continued to have seizures, 57.5% developed only focal aware seizures. Current driving regulations may be unduly restrictive for patients with gliomas.
The Identification and Validation of Plasma Membrane Proteins as Potential Therapeutic Targets for Histone H3 Mutant Paediatric High-Grade Gliomas
Authors: Snary Anya , Haque Farhana , Pickering James , Rahman Ruman , Grundy Richard , Layfield Robert
Published: October 2022

AIMS

Paediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death in children. Histone H3.3 mutations are an important hallmark of pHGG, but for which their underlying oncogenic mechanisms are incompletely understood. This research aims to identify potential molecular effectors in these tumours that may be therapeutically effective.

METHOD

To assess potential molecular effectors, we employed proteomic profiling using LC-MS/MS and determined plasma membrane proteins of the surfactome that are differentially expressed on the surface of H3.3 mutant (G34R, G34V), compared to H3.3-wildtype human glioma cells in culture.

RESULTS

Profiling of plasma membrane-enriched fractions identified 34 membrane proteins exclusively detected from H3 G34V mutant cells compared to H3 wild-type cells, and 10 membrane proteins exclusively detected from H3 G34R mutant cells, with 39 membrane proteins shared between both H3 G34R/V genotypes. One of these shared membrane proteins, GLUT1 (glucose transporter) has very recently been reported to be over-expressed and linked to tumour phenotypes in mouse glioma cells manipulated to carry the most common DIPG-associated H3.3-K27M mutation [Miya et al. Neuro-Oncology Advances 2021]. Here, we explore the functional significance of GLUT1 differential expression in H3.3 mutant (G34R, G34V) human glioma cells.
Glioma Espionage From Longitudinal CSF Proteomics
Authors: Riviere-Cazaux Cecile , Burns Terry
Published: October 2022

AIMS

Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response.

METHOD

Global proteomic analysis of CSF was performed on the Somalogic platform – an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples.

RESULTS

Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden.

CONCLUSION

Our data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal access to gliomas via Ommaya reservoirs.
Newly Diagnosed Brain Tumours: When Is a Staging CT Required?
Authors: El-Sayed Ali Ahmad Mahmoud , Doherty John Anthony , Konteas Anastasios Benjamin , Varasteh Amir Ali , Iqbal Noorulain , Vupputuri Hemanth , Brodbelt Andrew
Published: October 2022

AIMS

Newly diagnosed brain lesions (NBL) on imaging can be either primary or secondary in nature. Of these, only secondary brain lesions routinely require a staging CT chest, abdomen, and pelvis (CTCAP). But owing to lack of clear guidelines, all NBLs usually receive a staging investigation. This leads to over investigation of primary brain tumors. We sought to identify predictors of secondary brain lesions using CT head alone to guide the selection of patients for a CTCAP.

METHOD

Patients with NBLs referred to a tertiary Neurosurgical centre were reviewed. For protocol creation, data was collected from patients referred between July to December 2020, potential predictor variables were identified. Potential candidate protocols identified were assessed in a protocol-testing stage using data from a different set of patients. Sensitivity, specificity, and area under the curve (AUC) values were computed for each protocol.

RESULTS

The protocol-creation stage included 222 patients. Multivariate logistic regression analysis identified candidate protocols. This identified the most sensitive predictors of metastatic disease as : a previous history of cancer, multiple lesions, lesion size <4cm, and infratentorial location. A final protocol identified was found to have a sensitivity of 99.1% (AUC 0.704).

CONCLUSION

The use of the above protocol derived from this study would reduce unnecessary CTCAPs by 37.5-40% overall. Patients who do not fulfil at least one of the above said criteria on the first assessment should not have a CTCAP initially. This protocol reduces the financial and time costs from unnecessary CTCAPs as well as reduces patient exposure to radiation and contrast.
Patient and Service User Representation in Language Assessments on an Awake Craniotomy Pathway
Authors: Smith Georgette , Ughratdar Ismail , Wykes Victoria , Dawson Camilla
Published: October 2022

AIMS

Awake craniotomy (AC) with language mapping facilitates maximal safe intracranial tumour resection whilst preserving neurological function [1], and is associated with increased postoperative patient satisfaction and quality of life [2, 3]. We examine patients’ preoperative language assessment scores, alongside cultural and sociodemographic information to consider the impact on surgical planning and patient outcomes.

METHOD

A service evaluation of assessment tools was undertaken using clinical note audit and clinician reflections. Retrospective data collection from 48 patients assessed for AC with language mapping included language assessment scores, cultural and sociodemographic data, and surgical plan for awake or asleep tumour resection.

RESULTS

Analysis suggests language assessment scores may be influenced by a range of patient factors outside of the lesion location and its associated language deficits, including native language, age, ethnicity and religion.

CONCLUSION

Assessment scores influence a patient’s suitability for AC with language mapping and subsequent morbidity and mortality outcomes. Culture and sociodemographic background are integral to daily language use, and can therefore be expected to influence scores on language assessment tasks. This evaluation highlights the necessity for diversity of language use to be reflected in assessment tools used within an AC pathway.

REFERENCES

1. Hervey-Jumper, S.L. and M.S. Berger, Maximizing safe resection of low- and high-grade glioma. JNO, 2016.

2. Wahab, S.S., P.L. Grundy, and C. Weidmann, Patient experience and satisfaction with awake craniotomy for brain tumours. BJNS, 2011.

3. Coello, A.F., et al., Selection of intraoperative tasks for awake mapping based on relationships between tumor location and functional networks: A review. JNS, 2013.
Working Together to Accelerate the Preclinical to Clinical Translation of Drug Delivery Systems for Children’s Brain Tumours
Authors: Campbell Emma , Aquilina Kristian , Dandapani Madhumita , Walker David , Rahman Ruman
Published: October 2022

AIMS

Several techniques, such as intra-cerebrospinal fluid chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy, have the potential to transform the treatment of brain tumours in children. However, there have been very few clinical trials to evaluate these. We aim to address challenges in the pre-clinical to clinical research pathway for CNS drug delivery systems in order to increase the number of clinical trials in this area.

METHOD

In 2021, the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group established a Clinical Trials Working Group comprising international researchers and clinicians to address this issue.

RESULTS

This partnership highlighted the main challenges as: (1) a lack of specific funding for prototype development and/or scale-up for clinical trials; (2) difficulties in navigating the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multi-centric working. In response to this, we ran a workshop on ‘Clinical Trial Readiness’, attended by around 50 delegates (comprising clinicians, researchers, trial regulatory experts, policy makers, and representatives from funding organisations, brain tumour charities and industry).

CONCLUSION

We have now established speciality-specific working groups with the aim of producing recommendations around the use of preclinical models and drug delivery techniques according to brain tumour type. We have also created a ‘Roadmap’ document for preclinical to clinical translation, which will be freely shared with the neuro-oncology research community.
Surgery on a Primary Cranial Vault Lymphoma
Authors: de la Fuente Pablo , Rajwani Kapil , Sistiaga Iñigo , Lavrador Jose Pedro
Published: October 2022

AIMS

Unique cranial involvement in Lymphomas is extraordinary and when it occurs, it is usually accompanied by systemic involvement. The role of the surgery in these cases is still unclear.

METHOD

Case report of a 72-year-old female with a primary cranial vault lymphoma with primary surgical management at time of recurrence.

RESULTS

72-year-old female, with a background of treated breast cancer and ischemic heart, presented with a right parieto-occipital lytic bone lesion with a soft tissue mass with a diagnosis of Non-Hodgkin’s Lymphoma Type B, compatible with follicular lymphoma, with no other symptoms Systemic involvement was ruled out in PET CT bone marrow biopsy. First-line chemotherapy was precluded due to the cardiotoxicity, and she was started on Rituximab-Bendamustine and radiotherapy. PET-CT one year later shows local progression with lytic destruction. The MRI showed an imprint on the brain and a lesion in intimate contact with the superior longitudinal sinus. As an apparently localized lesion and the patient could not receive the optimal chemotherapy treatment, a craniectomy was proposed. Fifteen months after surgery the patient is free of disease on PET CT.

CONCLUSION

Primary cranial lymphoma is an unusual entity which precludes clear algorithms. The primary treatment is the chemotherapy, nonetheless, If the patient cannot receive the optimal treatment due to his background or in the presence of recurrent disease with limited treatment options, surgery should be considered if technically plausible and adequate to patient’s performance status.