bluuebunny/crossref_metadata_2025 huggingface dataset:
Residual effect of commonly used insecticides on key predatory mites released for biocontrol in strawberry
Authors: Busuulwa Allan , Riley Simon S , Revynthi Alexandra M , Liburd Oscar E , Lahiri Sriyanka
Published: October 2024

Florida is the second largest producer of strawberries in the United States. However, the production system faces numerous challenges, especially Scirtothrips dorsalis Hood (Thysanoptera: Thripidae) infestations. Management of this pest involves applying insecticides and use of predatory mites, particularly Amblyseius swirskii Athias-Henriot, Neoseiulus cucumeris Oudemans, and Neoseiulus californicus McGregor (Mesostigmata: Phytoseiidae). Strawberry growers in Florida are concerned about the compatibility of the commercial formulations of insecticides used in strawberry pest management with predatory mites. This study assessed the residual effect of commercial insecticides used in strawberry production on the survival, feeding, and oviposition of the 3 predators. Using Munger cells, predators were exposed to commercial formulations of spinetoram, cyantraniliprole, azadirachtin + pyrethrin, Beauveria bassiana, Cordyceps javanica, capsicum, garlic, and canola oil extracts, and water control. There was a gradual decline in the survival and feeding of predatory mites when exposed to all insecticides. Spinetoram had the highest impact on the survival and feeding of all predators compared to other insecticides, while C. javanica had the lowest impact. Cyantraniliprole and azadirachtin + pyrethrin significantly reduced predator survival after 72 h of exposure, whereas capsicum, garlic, and canola oil extracts caused a similar reduction after 96 h. All predators consumed low proportions of S. dorsalis across all treatments. Oviposition was low in all treatments, with no discernable variation among treatments. These results highlight the potential of using entomopathogenic fungi in conjunction with A. swirskii, N. cucumeris, and N. californicus for the management of S. dorsalis and T. urticae in strawberries.
Characterization of pectinase-producing Saccharomyces cerevisiae UCDFST 09-448 and its effects on cull peach fermentations
Authors: Gutierrez-Cano Aaliyah Raquel , Jones Bryce , Macario Jordan , Martin Sofia , Cardenas Derrick , Simpson Hannah , Boundy-Mills Kyria , Edwards Meredith Claire
Published: October 2024

Fermentation of pectin-rich biomass by Saccharomyces cerevisiae can produce bioethanol as a fuel replacement to combat carbon dioxide emissions from the combustion of fossil fuels. Saccharomyces cerevisiae UCDFST 09-448 produces its own pectinase enzymes potentially eliminating the need for commercial pectinases during fermentation. This research assessed growth, pectinase activity, and fermentative activity of S. cerevisiae UCDFST 09-448 and compared its performance to an industrial yeast strain, S. cerevisiae XR122N. Saccharomyces cerevisiae UCDFST 09-448’s growth was inhibited by osmotic stress (xylose concentrations above 1 M), ethanol concentrations greater than 5% v/v, and temperatures outside of 30°C–37°C. However, S. cerevisiae UCDFST 09-448 was able to consistently grow in an industrial pH range (3–6). It was able to metabolize glucose, sucrose, and fructose but was unable to metabolize arabinose, xylose, and galacturonic acid. The pectinase enzyme produced by S. cerevisiae UCDFST 09-448 was active under typical fermentation conditions (35°C–37°C, pH 5.0). Regardless of S. cerevisiae UCDFST 09-448’s limitations when compared to S. cerevisiae XR122N in 15% w/v peach fermentations, S. cerevisiae UCDFST 09-448 was still able to achieve maximum ethanol yields in the absence of commercial pectinases (44.7 ± 3.1 g/L). Under the same conditions, S. cerevisiae XR122N produced 39.5 ± 3.1 g/L ethanol. While S. cerevisiae UCDFST 09-448 may not currently be optimized for industrial fermentations, it is a step toward a consolidated bioprocessing approach to fermentation of pectin-rich biomass.

One-Sentence Summary

Saccharomyces cerevisiae UCDFST 09-448 demonstrates the potential to ferment pectin-rich biomass as part of a consolidated bioprocess, but is sensitive to industrial stressors.
Effects of the symbiotic bacteria, Caballeronia insecticola, on the life history parameters of Riptortus pedestris (Hemiptera: Alydidae) and their implications for the host population growth
Authors: Kho Jung-Wook , Jung Minhyung , Lee Doo-Hyung
Published: October 2024

This study aimed to investigate the effects of symbiosis on the life history of host insects and address their implications at the host population level. We evaluated the effects of symbiotic bacteria Caballeronia insecticola on its host Riptortus pedestris (Fabricus) (Hemiptera: Alydidae) from cohorts for nymphal development, adult survivorship, and female reproduction. Then, life table parameters were compared between symbiotic and apo-symbiotic groups, and the effects of symbiosis on the abundance of R. pedestris were simulated for varying proportions of symbiotic individuals in host populations. We found that symbiosis significantly accelerated the nymphal development and reproductive maturation of females. However, symbiosis incurred survival cost on adult females, reducing their longevity by 28.6%. Nonetheless, symbiotic females laid significantly greater numbers of eggs than the apo-symbiotic during early adult ages. This early reproductive investment negated the adverse effect of their reduced longevity, resulting in the mean lifetime fecundity to not significantly differ between the 2 groups. Indeed, total cohort fecundity of the symbiotic group was 1.3-fold greater than that of the apo-symbiotic group. Life table analysis demonstrated shorter generation time and greater population growth rate in the symbiotic population. Finally, the simulation model results indicate that an increase in the proportion of symbiotic R. pedestris favored the population growth, increasing the population size by 1.9 times for every 25% increase in the proportion of symbiotic individuals. Our study demonstrates that symbiont-mediated changes in the life history parameters of host individuals favor the host population growth, despite substantial reduction in the female longevity.
Idiopathic splenic infarcts in a patient with situs inversus totalis: a case report
Authors: Abunasser Bashar , Shabani Hisham Issa
Published: October 2024

Situs inversus totalis is a rare congenital abnormality characterized by a mirror-image transposition of both the abdominal and the thoracic organs. Splenic infarctions are considered a rare cause of abdominal pain, although the exact prevalence is unclear. We present a rare case of a 62-year-old male who presented to the emergency department with abdominal pain and was found to have large splenic infarcts with situs inversus totalis on computed tomography. The patient was admitted and treated conservatively. In conclusion, diagnosing situs inversus in cases of emergency is important because patients will present with abnormally located symptoms, and splenic infarction should be kept in mind when considering the differential diagnosis of abdominal pain despite its rarity.
A case of solitary metastatic colon adenocarcinoma of the sternum: an unusual metastatic site
Authors: Lahham Elias Edward , Al-Sa'ed Jamal Alddin Bilal Mohammad , Azzam Mosab Mohammed Saleh , Warda Ali Khalid Mahmoud Abu , Al Amleh Hisham
Published: October 2024

Colorectal cancer is a prevalent malignancy; it ranks as the third leading cause of cancer-related deaths globally. Despite the effectiveness of surgical intervention for primary tumors, ~30% of patients develop metastases, commonly in the regional lymph nodes, liver, lungs, and peritoneum. Bone metastasis is relatively rare but can occur, typically affecting vertebrae, pelvis, femur, and humerus. This study presents a 68-year-old patient with a history of locally advanced colon cancer who presented with a rapidly enlarging, painful sternal mass. Imaging and biopsy confirmed metastatic colon adenocarcinoma in the sternum. The patient was treated with radiation therapy, resulting in significant symptomatic relief and tumor reduction. This case highlights the rarity of sternal metastasis from colorectal cancer. Given the poor prognosis associated with skeletal metastases in colorectal cancer, this case emphasizes the need for vigilance in monitoring for atypical metastatic sites and the importance of tailored palliative care strategies.
The Meaning and Measure of Concordance Factors in Phylogenomics
Authors: Lanfear Robert , Hahn Matthew W
Published: October 2024

As phylogenomic datasets have grown in size, researchers have developed new ways to measure biological variation and to assess statistical support for specific branches. Larger datasets have more sites and loci and therefore less sampling variance. While we can more accurately measure the mean signal in these datasets, lower sampling variance is often reflected in uniformly high measures of branch support—such as the bootstrap and posterior probability—limiting their utility. Larger datasets have also revealed substantial biological variation in the topologies found across individual loci, such that the single species tree inferred by most phylogenetic methods represents a limited summary of the data for many purposes. In contrast to measures of statistical support, the degree of underlying topological variation among loci should be approximately constant regardless of the size of the dataset. “Concordance factors” (CFs) and similar statistics have therefore become increasingly important tools in phylogenetics. In this review, we explain why CFs should be thought of as descriptors of topological variation rather than as measures of statistical support, and argue that they provide important information about the predictive power of the species tree not contained in measures of support. We review a growing suite of statistics for measuring concordance, compare them in a common framework that reveals their interrelationships, and demonstrate how to calculate them using an example from birds. We also discuss how measures of topological variation might change in the future as we move beyond estimating a single “tree of life” toward estimating the myriad evolutionary histories underlying genomic variation.
Clinical study on the utility of allergy tests to detect IgE-mediated anaphylaxis after diclofenac etalhyaluronate administration
Authors: Okayama Yoshimichi , Hayama Koremasa , Takada Shuhei , Muramatsu Dai , Nobuoka Yuji , Yagami Akiko
Published: October 2024

Objectives

This study was conducted to investigate factors involved in anaphylaxis related to diclofenac etalhyaluronate (DEH) [product name: Joyclu® (JCL)] (containing DEH and macrogol 400), which is used to treat patients with osteoarthritis.

Methods

Patients with osteoarthritis were divided into two groups that had (experienced patients) or had not experienced anaphylactic symptoms after JCL administration (nonexperienced patients). Five tests performed to assess factors related to anaphylaxis consisted of a skin prick test as the primary endpoint and the other tests including basophil activation test, allergen-specific IgE tests using enzyme-linked immunosorbent assay or immunochromatographic kits, and genetic study were secondary endpoints.

Results

The skin prick test showed 4 (wheal)/7 (erythema) of 15 experienced patients and 0/3 of 19 nonexperienced patients were positive for any of the test reagents containing DEH. The basophil activation test showed two experienced patients were positive for test reagents containing DEH. DEH- and diclofenac-allergen-specific IgE were detected in 3 and 1 of 12 experienced patients, respectively. No clear results were shown in the other tests.

Conclusions

DEH may be the main factor involved in the development of anaphylaxis. The skin prick test was more sensitive than the basophil activation and allergen-specific IgE tests for identifying factors associated with anaphylaxis.
SpatialRef: a reference of spatial omics with known spot annotation
Authors: Cui Ting , Li Yan-Yu , Li Bing-Long , Zhang Han , Yu Ting-Ting , Zhang Jia-Ning , Qian Feng-Cui , Yin Ming-Xue , Fang Qiao-Li , Hu Zi-Hao , Yan Yu-Xiang , Wang Qiu-Yu , Li Chun-Quan , Shang De-Si
Published: October 2024

Spatial omics technologies have enabled the creation of intricate spatial maps that capture molecular features and tissue morphology, providing valuable insights into the spatial associations and functional organization of tissues. Accurate annotation of spot or domain types is essential for downstream spatial omics analyses, but this remains challenging. Therefore, this study aimed to develop a manually curated spatial omics database (SpatialRef, https://bio.liclab.net/spatialref/), to provide comprehensive and high-quality spatial omics data with known spot labels across multiple species. The current version of SpatialRef aggregates >9 million manually annotated spots across 17 Human, Mouse and Drosophila tissue types through extensive review and strict quality control, covering multiple spatial sequencing technologies and >400 spot/domain types from original studies. Furthermore, SpatialRef supports various spatial omics analyses about known spot types, including differentially expressed genes, spatially variable genes, Gene Ontology (GO)/KEGG annotation, spatial communication and spatial trajectories. With a user-friendly interface, SpatialRef facilitates querying, browsing and visualizing, thereby aiding in elucidating the functional relevance of spatial domains within the tissue and uncovering potential biological effects.
Mycobacterium smegmatis NucS-promoted DNA mismatch repair involves limited resection by a 5′-3′ exonuclease and is independent of homologous recombination and NHEJ
Authors: Rivera-Flores Iris V , Wang Emily X , Murphy Kenan C
Published: October 2024

The MutSL mismatch repair (MMR) systems in bacteria and eukaryotes correct mismatches made at the replication fork to maintain genome stability. A novel MMR system is represented by the EndoMS/NucS endonuclease from Actinobacterium Corynebacterium glutamicum, which recognizes mismatched substrates in vitro and creates dsDNA breaks at the mismatch. In this report, a genetic analysis shows that an M. smegmatis ΔnucS strain could be complemented by expression of wild type NucS protein, but not by one deleted of its last five amino acids, a region predicted to be critical for binding to the β-clamp at the replication fork. Oligo-recombineering was then leveraged to deliver defined mismatches to a defective hygromycin resistance gene on the M. smegmatis chromosome. We find that NucS recognizes and repairs G-G, G-T, and T-T mismatches in vivo, consistent with the recognition of these same mismatches in C. glutamicum in vitro, as well as mutation accumulation studies done in M. smegmatis. Finally, an assay that employs an oligo that promotes the generation of two mismatches in close proximity on the chromosome shows that a NucS-promoted cut is processed by a 5′–3′ exonuclease (or 5'-Flap endonuclease) and that NucS-promoted MMR is independent of both homologous recombination and non-homologous end-joining.
PL01.4.A COMPUTATIONAL HISTOPATHOLOGY ENABLES HIGH-GRANULARITY DIAGNOSTICS IN CNS TUMOURS
Authors: Shmatko A , Jin D , Patel A , Rahmanzade R , Wick W , Krieg S , Pfister S M , Jones D T W , von Deimling A , Gerstung M , Sahm F
Published: October 2024

BACKGROUND

The recent WHO classification of CNS tumours has increased the number of molecular markers recommended for making a WHO-compatible diagnosis. Particularly, DNA methylation-based classification pioneered by the Heidelberg MNP classifier has emerged as a powerful tool for CNS tumour diagnostics. However, high costs, both in terms of time and resources, along with the need for skilled personnel and expensive equipment, have limited the adoption of such techniques to larger centres. Computational methods like deep learning have proven useful in tasks such as tumour subtyping, identifying genetic alterations and predicting treatment responses. The recent advent of self-supervised learning and multiple-instance learning (MIL) has enhanced the accuracy and generalisation of these models, simultaneously reducing the dataset size requirements, thus bringing computational histopathology closer to clinical applications.

MATERIAL AND METHODS

To enable broader accessibility of precision diagnostics for CNS tumours and alleviate the need for molecular profiling, we introduce Paiean (Precision AI-enabled Neuropathology) - a computational histopathology pipeline that predicts the diagnostically relevant classes in line with the Heidelberg MNP classifier using only H&E stained whole-slide images (WSI). We designed a neural network architecture implemented in a MIL paradigm. Paiean employs a CTransPath pretrained feature extractor to identify and analyse relevant histological patterns and was fine-tuned on an in-house dataset of CNS tissue WSIs using the MoCo v3 contrastive objective. We trained the model on a dataset of 8,000 H&E stained FFPE WSIs with matched methylation data from the Dept. of Neuropathology, University Hospital Heidelberg. We validated the model on 5 independent external datasets. Additionally, we compared the model to evaluations by 9 board-certified pathologists from across the world.

RESULTS

Paiean could reliably predict 108 classes of CNS tumours in 72.19% cases. Moreover, for high-confidence predictions (confidence > 0.5), the accuracy increased to 87.52%. We achieved an accuracy of 65.12% on the multi-center external datasets. The model outperformed the human evaluators by an average of 30.17%.

CONCLUSION

Our work demonstrates that deep learning can supplement conventional methods for molecular diagnostics in CNS tumours. Paiean requires only H&E WSI, covers 108 diagnostically relevant tumour types and has a turnaround time of under an hour from sample to result. We provide an interface that can be easily run on consumer-grade hardware without extensive bioinformatics expertise. Since H&E slides are readily used in routine tumour diagnostics worldwide, Paiean presents a rapid and cost-effective tool to incorporate molecular information into diagnostic decisions, thereby making precision medicine accessible worldwide.
JS03.7.A COMBINATION OF CDK4/6 AND MEK INHIBITION INCREASES ANTITUMOR EFFECTS IN PEDIATRIC HIGH-GRADE GLIOMA HARBORING BRAF MUTATION AND CDKN2A/B LOSS
Authors: Mayr L , Mager L , Lang A , Madlener S , Gabler L , Bruckner K , Machreich S , Jaunecker C , Senfter D , Kirchhofer D , Lämmerer A , Zeitler G , Dorfer C , Haberler C , Schwark K , Lau B , Müllauer L , Koschmann C , Berger W , Gojo J , Lötsch-Gojo D
Published: October 2024

BACKGROUND

Pediatric high-grade gliomas (pHGG) comprise a heterogenous group of tumors characterized by rapid growth and dismal overall survival. Besides maximum safe resection, irradiation and chemotherapy, molecularly-defined therapeutic interventions are still missing. BRAFV600E mutations are detected in 5-10% of pHGG and this subgroup frequently harbors a concurrent homozygous CDKN2A/B loss. Taking advantage of those molecular alterations is of utmost importance to improve overall survival in these patients. Thus, we hypothesize that a combination of MEK and CDK4/6 inhibition lead to prolonged anti-tumor effects in this patient subgroup when compared to monotherapy.

MATERIAL AND METHODS

Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the efficacy of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combined with the MEK inhibitor trametinib. Drug response, induction of apoptosis, cell cycle alterations and senescence were evaluated upon short- and long-term exposure using cell-based assays. Effects on intracellular signaling cascades were determined by western blot and immunostainings in cell and patient-derived xenograft (subcutaneous and orthotopic) models. Clinical efficacy of combined treatment was further investigated in one patient suffering from progressive metastatic BRAF-altered anaplastic pleomorphic xanthoastrocytoma (aPXA).

RESULTS

Besides trametinib, the investigated cell models showed the highest sensitivity to abemaciclib, thus we assumed that combination of these two inhibitors would be most suitable in vitro. The simultaneous application of both drugs induced apoptosis and the effect on tumor cell senescence was even superior with the combined treatment. Regarding signal transduction, solely the combination of MEK and CDK4/6 inhibitors reduced PI3K activation at the level of S6. To confirm our findings, in vivo experiments in PDX models were conducted. Significantly increased overall survival and antitumor effects were observed with the combination of both inhibitors when compared to single-agent treatment. Corroboratively, one patient suffering from progressive metastatic aPXA with BRAF mutation and CDKN2A/B loss was successfully treated with trametinib and ribociclib showing stable diseases for two years.

CONCLUSION

Summarizing, our results suggest that combined treatment with MEK and CDK4/6 inhibitors represent a promising treatment strategy in pHGG harboring simultaneous BRAF mutation and CDKN2A/B loss.
JS06.6.A COPENHAGEN GRADING FOR MENINGIOMA
Authors: Haslund-Vinding J L , Skjoth-Rasmussen J , Law I , Fugleholm K B , Meling T R , Poulsgaard L , Maier A D , Larsen V A , Forsse A , Henriksen O M , Madsen K , Mirian C , Poulsen F R , Förrander P , Santarius T , Bartek J J , Scheie D , Ziebell M , Kristensen B W , Mathiesen T
Published: October 2024

BACKGROUND

The extent of meningioma resection is the most fundamental risk factor for recurrence and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between “gross total removal” and “subtotal removal”, while the latter comprises a five-tiered differentiation of the surgeon’s impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas.

OBJECTIVE

To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68Ga DOTATOC PET, we propose “Copenhagen Grading” for meningiomas.

PRELIMINARY RESULTS

Since April 2021, Copenhagen Grading has been implemented prospectively as a clinical standard at Rigshospitalet, Copenhagen, with 264 patients enrolled thus far. DOTATOC PET was used for follow-up in 212 subjects, while resection margin biopsies were obtained from 90 subjects. DOTATOC-PET revealed residual tumor in 33% (55/168) of cases where MRI results were inconclusive and in 28% (47/168) of cases where MRI showed no residual tumor.

CONCLUSION

Copenhagen Grading offers a comprehensive, logical, and reproducible means of defining resection extent, showing potential as the most sensitive and specific grading. Further long term evaluation of the clinical implication of biopsies and the cost-effectiveness of DOTATOC PET is necessary during the prospective implementation.
JS07.6.A MULTI-OMICS AND DRUG RESPONSE ASSESSMENTS IN LONGITUDINAL PATIENT AVATARS UNVEIL PATIENT-SPECIFIC RECURRENCE TRAJECTORIES AND DRUG SUSCEPTIBILITIES IN GLIOBLASTOMA
Authors: Lipsa A , Nosirov B , Ermini L , Hau A , Klein E , Yabo Y A , Mittelbronn M , Hertel F , Nazarov P V , Niclou S P , Golebiewska A
Published: October 2024

BACKGROUND

Glioblastomas (GBMs) have the worst prognosis of all adult brain tumours. Despite the aggressive standard-of-care, including surgery, radio- and chemotherapy, tumours inevitably recur and median survival remains at 18 months. GBMs exhibit complex changes at recurrence, although no common evolutionary trajectory has been identified yet. Such molecular evolution may lead to functional changes in drug response patterns. Investigations of longitudinal heterogeneity of paired primary-recurrent tumours using high resolution multi-omics profiling combined with functional investigations in matched patient avatars can provide clinically-relevant insights into tumour evolution at the individual patient level.

MATERIAL AND METHODS

We applied a cohort of longitudinal patient tumors and preclinical models derived thereof, propagated as primary organoids and orthotopic xenografts. Our cohort includes a unique collection of paired primary-recurrent patient avatars derived from 8 patients during their standard-of-care disease trajectory. We performed a comprehensive multi-omics profiling, including transcriptomics (bulk and single cell RNA-seq), epigenomics (DNA methylation arrays), genomics (targeted DNA-seq) and proteomics (LC-MS) to identify molecular evolution of tumors at recurrence. We further carried out an ex-vivo functional drug screen with a pharmacologically diverse 1482 compound library targeting cancer pathways and epigenetic modifiers.

RESULTS

High-resolution multi-omics analysis of longitudinal patient tumours and patient avatars identified patient-specific evolution of the primary tumours at recurrence following surgical resection and treatment pressure. While certain GBMs recurred without major molecular adaptation, others showed significant (epi)genetic and transcriptomic evolution towards new genetic clones and/or transcriptomic states. Majority of drug responses were similar in primary and recurrent tumours and were patient-specific. Interestingly, we observed selective susceptibilities to several epigenetic modifiers, especially Histone Deacetylase (HDAC) and Aurora Kinase (AURK) inhibitors in certain primary tumours, which were lost at recurrence.

CONCLUSION

Our study demonstrates the importance of combined omics and functional profiling to reveal clinical implications of longitudinal evolutionary trajectories in GBMs. Our findings imply that the impact of potentially effective drugs may differ between newly diagnosed and recurrent GBMs that might have implications in precision therapy strategies.
OS01.5.A MEASURABLE DISEASE AS BASELINE CRITERION FOR RESPONSE ASSESSMENT IN GLIOBLASTOMA TRIALS - A COMPARISON OF THE MRI-BASED (RANO 2.0) VERSUS PET-BASED (PET RANO 1.0) ASSESSMENT
Authors: Müller K J , Forbrig R , Reis J , Wiegand L , Barci E , Kunte S , Kaiser L , Schönecker S , Schichor C , Harter P , Thon N , von Baumgarten L , Preusser M , Albert N L
Published: October 2024

BACKGROUND

The baseline criterion for response assessment in IDH-wildtype glioblastoma relies on measuring contrast enhancement, known as ‘measurable disease’ on MRI. Recently, criteria based on amino acid PET have been proposed for response assessment in clinical glioblastoma trials (PET RANO 1.0 criteria). Here, we compare ‘measurable disease’ as defined by PET RANO 1.0 criteria with the standard MRI-based RANO 2.0 criteria in patients with newly diagnosed IDH-wildtype glioblastoma.

MATERIAL AND METHODS

In this retrospective single-center study, we identified patients with newly diagnosed IDH-wildtype glioblastoma who underwent [18F]FET PET and MRI after resection or biopsy (if non-operable) and before chemoradiotherapy. This timepoint aligns with the baseline recommended by PET RANO 1.0. Two independent investigators analyzed ‘measurable disease’ according to PET RANO 1.0 versus MRI-based RANO 2.0 criteria. Additionally, lesion size and uptake intensity, including maximal and mean target-to-background ratio (TBRmax, TBRmean) were assessed.

RESULTS

We evaluated 132 patients (median age 60.5 years, 40.2% females) with 87 cases after biopsy and 45 after resection. Using RANO 2.0, a total of 49/132 (37.1%) patients had measurable disease (median sum of maximum perpendicular diameters: 36.3mm). However, with PET RANO 1.0, a significantly higher proportion (117/132, 88.6%, p<0.001) had measurable disease (median TBRmax: 3.4; median TBRmean: 2.0; median PET volume: 17.6cm3). None of the 15 patients without measurable disease on PET had measurable disease on MRI, while 68/83 (81.9%) of patients without measurable disease on MRI exhibited measurable disease on PET. Conclusion: PET RANO 1.0 identifies a significantly higher number of patients with ‘ measurable disease’ compared to conventional MRI-based criteria in the perioperative period of newly diagnosed glioblastoma. PET-based assessment may thus serve as a novel baseline parameter for evaluating treatment response and outcome in glioblastoma trials, that may allow enrollment of larger patient populations. Further validation in prospective trials is warranted.
OS02.6.A COORDINATION OF CARE IN THE CONTEXT OF PRIMARY BRAIN TUMOURS: HEALTHCARE PROFESSIONALS’ EXPLORATION OF THE UNSPOKEN IMPACT AND CLINICAL IMPLICATIONS
Authors: Jeon M S , Shaw J , Banks H , Legge D M , He S , Carlick T , Koh E S , Halkett G , Kelly B , Pinkham M B , Ownsworth T , Chan R J , Dhillon H
Published: October 2024

BACKGROUND

People with primary brain tumours (PwBT) and their families expereince high distress and face challenges navigating the disease, healthcare system, treatment, and/or survivorship. Coordination of care is an approach to achieving continuous, timely care according to individual care needs of PwBT. Within the Brain Cancer Rehabilitation, Assessment, Interventions for Survivorship Needs (BRAINS) program, we aimed to explore healthcare professionals’ (HCPs) practices and perceptions about neuro-oncology care coordination (NOCC).

MATERIAL AND METHODS

We conducted a qualitative study using semi-structured interviews via videoconferencing. Participants were HCPs involved in clinical neuro-oncology care. Interviews were audio-recorded and transcribed verbatim. Data were analysed thematically using interpretive description, following COREQ guidelines for conducting and reporting qualitative research.

RESULTS

We interviewed 12 HCPs from Australia and Aotearoa New Zealand between June and November 2023. The median interview duration was 58 minutes. Participants had a median of 13 years of clinical experience in neuro-oncology across medical, nursing, and allied health disciplines. NOCC models were not standardised. Often they were not clearly established and depended on HCPs’ knowledge, experience, and skillsets for triaging care or managing advanced illnesses. HCPs typically oversaw NOCC in either the neurosurgical or oncology care phases but not both. We identified five themes related to NOCC as perceived by HCPs: 1) Vulnerable and complex: PBT is a unique cancer generating pervasive, multifaceted disabilities; 2) Tailored coordination: Shaping and tailoring NOCC is in the best interests of PwBT and families; 3) Unfunded support: Care needs warrant unfunded proactive support; 4) Role limitations: Limited resources impact HCPs’ capacity to deliver the optimal standard of care; and 5) Emotionally demanding: HCPs manage emotional weight with limited support.

CONCLUSION

PwBT experience a unique and complex set of care needs requiring specialist skills and knowledge beyond general oncology care coordination. NOCC encompasses continuous coordination of multidisciplinary care to optimise functional living for PwBT. Recognising the NOCC role in managing a vast array of issues, better support infrastructure with training and resources for HCPs is needed to retain HCPs and prevent burnout, which will provide greater access to NOCC for PwBT and carers. The findings will inform further research to identify support, training and resource needs for HCPs and implement appropriate interventions.

FUNDING

The study is funded by the MRFF Australian Brain Cancer Mission Brain Cancer Survivorship Grant.
OS03.6.A MITOCHONDRIA TRANSFER IN GBM IS MEDIATED BY TGF-Β AND PROMOTES INCREASED INVASIVENESS
Authors: Moreino S S , Storevik S , Pinaz F , Lourido M C , Han J , Augustsson M T , Sarnow K , Joseph J V , Ystaas L A R , Neises L , Meiser J , Bjerkvig R , Daubon T , Hossain J A , Miletic H
Published: October 2024

BACKGROUND

Acquisition of intact mitochondria from the tumor microenvironment (TME) is a ubiquitious phenomenon in tumors of glioblastoma multiforme (GBM),promoting mitochondrial respiration and metabolic pathways tied to proliferation and tumorigenicity 1. The Transforming growth factor β (TGFβ) pathway is a major molecular pathway upregulated in GBM compared to low grade gliomas 2 and recent studies have shown its involvement in invasion associated microtube (MT) formation 3. We hypothesized that TGFβ affects the mitochondria transfer process between GBM and members in the TME, namely astrocytes. We speculated that mitochondria transfer would lead to increased invasiveness as oxidative metabolism has been previously linked to invasion 1. Furthermore, we postulated that inducing metabolic stress conditions via mitochondria depletion would have an impact on the GBM-TME mitochondria transfer process.

METHODOLOGY

We utilised specifically transduced cell lines, immunofluorescence, confocal imaging and flow cytometry to measure mitochondria transfer under TGFβ treatment, MT formation and downstream SMAD signaling. Invasion data was elucidated via collagen invasion assays. Mitochondria depletion experiments in vitro were conducted using electron transport chain inhibitor treatment and flow cytometry. Orthotopic xenograft models were utilised to study this mitochondria depletion in vivo, and immunohistochemical analyses were performed to quantify mitotransfer.

RESULTS

Our in vitro results show that treatment of GBM - astrocyte cocultures with TGFβ directly impacted mitotransfer rates, MT formation and downstream SMAD signaling. Results obtained from collagen assays show promoted invasion in GBM with acquired mitochondria from the TME. Our mitochondria depletion model experiments show an amplified transfer of mitochondria from the TME by mitochondria deficient GBM cells - further characterizing the reliance of GBM on this process to promote its aggressive tumorigenic phenotype.

CONCLUSION

We identified a new mediating role of TGFβ in GBM interactions with the TME and canonical SMAD as a specific downstream signaling pathway involved. Our collagen invasion and mitochondria depletion studies also demonstrated the importance of mitochondria transfer from TME astrocytes to GBM in cellular functions related to proliferation, invasion and cell rescue.

REFLECTION

The findings of our study provide new insights into GBM disease progression and therapy resistance, indicating new opportunities for treatment development.
OS04.5.A SEXUALITY IN PATIENTS WITH LOW-GRADE GLIOMAS
Authors: Buunk A M , Siebenga F F , Bosma-Bleeker M H , Spikman J M
Published: October 2024

BACKGROUND

Patients diagnosed with a low-grade glioma (LGG) face various challenges that influence their daily functioning, such as mood disorders, cognitive decline and fatigue. However, little is known about problems concerning sexuality and intimacy in patients with LGG, although these can have a profound negative impact on quality of life and well-being. Also, related factors (disease characteristics, cognitive functions, emotional problems) are unknown. Therefore, the aim of the present study was twofold: 1) investigate changes in sexuality after diagnosis of and surgery for LGG, and 2) examine if sexuality changes are related to disease characteristics (tumor volume and localisation), cognitive impairments and mood problems.

MATERIAL AND METHODS

Patients with diffuse oligodendrogliomas and astrocytomas (WHO grades II and III) were included. After surgery, before the start of adjuvant therapy, cognitive functions and mood were investigated with neuropsychological tests and questionnaires respectively. At least 3 months after proton therapy, sexuality was investigated with the Brain Injury Questionnaire of Sexuality (BIQS), with lower scores indicative of decreases in sexual functioning compared to pre-diagnosis. The subscales Sexual Functioning (8 items, range 8-40, score between 8-23 = indicative for negative change) and Relationship Quality & Self-Esteem (5 items, range 5-25, score between 5-14 = indicative for negative change) were used. Tumor volume and location were recorded. Descriptive statistics, between-group comparisons and correlational analyses were used.

RESULTS

46 patients with LGG were included (mean age = 43.2 years, 32.6% female). Compared to pre-diagnosis, 71.7% of all patients reported decreased sexual functioning and 54.3% lower relationship quality and self-esteem. On item level, most frequent changes were decreased sex drive (41.3%), lower importance of sexuality (43.5%), decreased ability to give partner sexual satisfaction (47.8%), and lower frequency of sexual activities (67.4%). Correlational analyses and between-group comparisons yielded no significant associations between sexuality changes and tumor volume, localisation, cognitive impairments, and mood problems.

CONCLUSION

Changes in sexuality were found in over 70% of the patients with LGG, with most frequent changes being lower frequency and the decreased ability to give a partner sexual satisfaction. Decreases compared to pre-diagnosis did not appear to be closely connected to disease-related, psychological or cognitive factors. Consequently, our results emphasize the need to consider sexual health in all patients with LGG in clinical practice, as neglecting sexuality can lead to unnecessary sexual problems, feelings of loneliness and isolation. Future studies could examine the effect of adjuvant therapies, such as proton therapy, on sexuality more closely.
OS06.8.A PROSPECTIVE STUDY ON THE IMPACT OF THE GUT MICROBIOME COMPOSITION TO PATIENT’S RESPONSE TO STANDARD TREATMENT IN PCNSL
Authors: Hernández-Verdin I , Kirasic E , Mokhtari K , Barillot N , Rincón de la Rosa L , Sourdeau E , Abada Y , Le Tarff-Tavernier M , Choquet S , Houillier C , Hoang-Xuan K , Alentorn A
Published: October 2024

BACKGROUND

Gut microbiota has gained attention as a potential modulator of occurrence, progression, and response to cancer therapy, with host immune regulation as one potential mechanism. Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma whose treatment relies on a high-dose methotrexate (HD-MTX) regimen with or without consolidation. However, whether there is a specific microbiota composition association with treatment response and clinical outcomes remains incompletely understood.

MATERIAL AND METHODS

To identify the relationship between gut microbiome composition and response standard treatment in patients with PCNSL, we conducted a prospective study of PCNSL patients, included in the clinical trial NCT02313389 and the ancillary study NCT04253496 from 2020 to 2023 (patients aged more than 60 years, HD-MTX based induction and randomized HD-MTX-based maintenance versus follow-up without consolidation). Stool and cerebrospinal fluid (CSF) samples (n=49) were collected before (n=35) or after (n=14) therapy initiation to perform metagenomic and flow cytometry analyses. Clinical data, including treatment response, progression-free survival (PFS), and overall survival (OS), were collected and correlated with microbiome composition and immune cell content in CSF.

RESULTS

Analysis of paired samples (before versus after HD-MTX), revealed slight changes in microbial composition, especially the loss of a bacteria belonging to the Verrucomicrobiota Phylum. Unsupervised clustering on microbial data revealed two microbial communities associated with significantly distinct PFS (33.65 vs 7.60 months, p=0.001) and OS (36.75 vs 23.95 months, p=0.005) in PCNSL patients. Linear discriminant analysis Effect Size and differential abundance analysis between these communities revealed a specific organism belonging to the Bacteroidota Phylum whose enrichment is associated with improved OS and PFS at both univariate and multivariate models. Further stratifying patients according to this bacteria content showed an association with CD8 T cell infiltration to the CSF, suggesting a link between host immune cell regulation and gut microbiome composition.

CONCLUSION

Our findings suggest that gut microbiome communities may influence responses to standard treatment and clinical outcomes in PCNSL patients. Moreover, the identification of this particular microorganism could potentially provide a basis for patient stratification and guide personalized therapeutic strategies. We are currently working in a validation cohort to reinforce our findings and to elucidate the mechanisms underlying the interaction between the gut microbiome, the host immune regulation, and the treatment response.
OS07.6.A CONNEXIN-MEDIATED NETWORKS IN GLIOBLASTOMA COMMUNICATION
Authors: Strobel H , Mulaw M , Karpel-Massler G , Peraud A , Debatin K , Westhoff A
Published: October 2024

BACKGROUND

Recent data suggest that Glioblastoma (GB), a highly aggressive malignant brain tumor, mimics cellular interactions found in healthy brain structures. GB cells exhibit, among other types of interaction, extensive membrane protrusions linked through gap junctions (GJs), tightly regulated intercellular channels predominantly comprised of connexins (Cxs). These channels facilitate the exchange of small molecules and also provide platforms for signaling hubs. Consequently, GJs/Cxs interconnect GB cells into expansive communicative networks that substantiate tumor growth, migration, and influence the response to injury. In this investigation, we delineated the precise composition of Cxs in brain tumors, with a specific emphasis on GB, unraveling their nuanced functional roles.

MATERIAL AND METHODS

Using our exclusive repository of primary brain tumor specimens, we screened for the expression of all 21 known Cxs. By comparing our findings with publicly available RNA sequencing data sets and performing various in silico analyses, we identified Connexin 26 (Cx26) as an interesting candidate. The role of Cx26 in a defined signaling network was further elucidated by pharmacological modulation as well as genetic knock-out models.

RESULTS

We found a multitude of Cxs expressed in brain tumors, many of them dysregulated when compared to their expression in healthy brain cells. Additionally, by utilizing in silico analyses of publicly accessible RNA sequencing datasets, the expression of Cx26 emerges as a potential biomarker, correlating significantly with the overall survival of GB patients. Notably, subsequent analysis affirms that Cx26 expression is highest in grade IV brain tumors and in GBs, it exhibits a pronounced association with the mesenchymal subtype. Within the tumor, its expression is most notably concentrated in the tumor core and aligns with the recently described Connectivity Signature. The genetic manipulation of Cx26 exerted a profound impact on cellular behavior. Notably, the knock-out of Cx26 significantly impeded the cells’ ability to establish morphological networks when cultured in the presence of an extracellular matrix substrate. Furthermore, pharmacological modulation of these cells suggests Cx26 as a prospective mediator in facilitating TGF-β1-associated cell-cell communication.

CONCLUSION

Cx26 is a novel mediator of connectivity that facilitates cell-cell interaction in the recently described network that characterizes a particular aggressive GB subpopulation. This effect seems to be associated with the tight regulation of the TGF-β1 signaling cascade.
OS07.7.A DISSECTING SPATIAL DIVERSITY OF GLIOBLASTOMA GENOTYPES
Authors: Zhang J , Joshi T , Hambardzumyan D , Heiland D
Published: October 2024

BACKGROUND

Glioblastoma (GBM) remains an intractable cancer characterized by significant inter- and intra-patient heterogeneity. Recent research has established connections between key genetic drivers and distinct transcriptional profiles in GBM, yet the interactions between genetic changes and the transcriptional and spatial heterogeneity remain unclear. This study used genetically engineered mouse models, coupled with spatially resolved and single-cell RNA sequencing, to explore how specific genetic alterations influence the tumor microenvironment (TME) and cellular responses spatially.

MATHODS

We used nestin-Tva C57BL/6 mice and generated de novo GBM using overexpression of oncogenes in combinations with short hairpin RNAs (shRNAs) or deletion to various tumor suppressors, including Tp53, Cdkn2A, and Pten. We modeled key driver mutations for GBM: PDGFB, NF1, and EGFR. We conducted single-cell RNA sequencing, combined with spatially resolved transcriptomics and proteomics. Data integration techniques, including horizontal (mutual nearest neighbors) and vertical (weighted nearest neighbors) approaches, were used and analyzed with the SPATA2 software. Advanced computational methods, such as graph neural networks and single-cell deconvolution, were applied to examine GBM genotypes and the spatial variability within tumors and their TMEs.

RESULTS

Our findings revealed persistent cellular heterogeneity among tumor cells under various genetic conditions. However, specific genetic alterations influenced the cells toward dominant transcriptional states. NF1 and EGFR mutations resulted in shifts towards MES and AC-like states, respectively, unlike PDGFB, which promoted a NPC/OPC-like state. These transcriptional shifts were strongly associated with distinct microenvironmental changes, such as enhanced neuronal signaling in PDGFB-driven GBMs versus pronounced immune infiltration in NF1 and EGFR models. Utilizing weighted co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA) alongside spatial-niche deconvolution, we identified a mesenchymal transition leading to an immunosuppressive TME in NF1-driven GBMs and increased lymphocyte presence in EGFR-amplified GBMs, especially around blood vessels. Similar spatial patterns were observed in human spatially resolved transcriptomic data, highlighting the complexity and variability of genetic drivers in human GBMs.

CONCLUSION

Our genetically engineered mouse models provide a valuable platform for investigating GBM with defined driver mutations. By leveraging sophisticated analytical techniques and computational modeling, this study underscores the potential to elucidate the interactions between genetic drivers and the tumor microenvironment. Our approach paves the way for developing targeted therapies and precision medicine strategies in GBM.