bluuebunny/crossref_metadata_2025 huggingface dataset:
Opportunities and risks of double cropping in southwestern France with a focus on soybean and sunflower crops
Authors: Pitchers Julie , Ferrand Nicolas , Pull Manon , Minette Sébastien , Abella Mathieu , Debaeke Philippe
Published: August 2023

Growing a second food, fodder or bioenergy crop during the fallow period commonly refers to sequential double cropping or relay cropping practices, as a function of sowing date (following or within the primary crop, respectively). Such practice may generate an additional income while supplying support and regulation services. As such, it could be referred as a form of ecologically intensive agriculture but also an opportunity offered by climate change. The decision-making process in the adoption of double cropping relies on many factors related to soil and climate conditions, but also on profit expectation and risk perception. The CASDAR project “3C2A: Three crops in two years” (2019–2023) strived to create references for sequential double cropping in the South-West of France, which encompasses the regions of Nouvelle-Aquitaine and Occitanie. The project focused mainly on grain crops and raised the interest of the use of oil-protein crops such as soybean (Glycine max(L.) Merrill) and sunflower (Helianthus annuusL.) for such practice. As a preliminary contribution of 3C2A project, this paper aims at illustrating the potential interest of soybean and sunflower as double crops in the South-West of France through a qualitative analysis of farmers’ perceptions about the risks and opportunities of double-cropping completed by a 4-years on-farm evaluation of agronomic and economic performances of this practice (110 fields).
Normaldruckhydrozephalus
Authors: Kehler Uwe , Hattingen Elke
Published: August 2023

Für Diagnostik, Differenzialdiagnostik und Differenzialtherapie des Normaldruckhydrozephalus ist die Bildgebung entscheidend. Auch wenn die Therapie eines Normaldruckhydrozephalus nicht
erfolgreich sein sollte, werden zahlreiche Fragen an den Radiologen gestellt. Der Artikel gibt eine Übersicht über das Krankheitsbild des Normaldruckhydrozephalus und die speziellen prä- und
postchirurgischen Anforderungen an die Bildgebung.
Systemtherapie des Peniskarzinoms – neue Konzepte? Neue Erfolge?
Authors: Hakenberg Oliver , Dräger Desiree Louise
Published: August 2023

Die systemische Chemotherapie wird seit Jahren mit beim metastasierten Peniskarzinom angewandt, jedoch nur mit begrenztem Erfolg. Ihre Bedeutung liegt überwiegend im Rahmen der multimodalen Therapie bei lymphogener Metastasierung in Zusammenhang mit radikaler Lymphknotenchirurgie. Bei begrenztem Lymphknotenbefall kann die Kombination von operativer Therapie mit cisplatin- und taxanhaltigen Dreifachkombinationen kurativ sein.

Fortschritte im Verständnis der molekularen Veränderungen beim Peniskarzinom und die Suche nach potenziellen Therapietargets haben zur Auflegung zahlreicher Studien geführt. Trotz Hinweisen auf die Wirksamkeit von Immuntherapeutika haben sich bislang jedoch keine wesentlichen therapeutischen Verbesserungen für die klinische Praxis ergeben.
Organerhaltende Therapie als wichtigste Option in der Behandlung des Primärtumors des Peniskarzinoms
Authors: Protzel Chris , Kutschke Richard , Eckert Marie-Luise
Published: August 2023

Die Therapie des Peniskarzinoms stellt eine relevante Herausforderung für Therapeuten wie für Patienten dar. Dabei muss der Schwerpunkt nicht nur auf operative Techniken, sondern sehr viel mehr auf Patienteninformation und gemeinsame Therapieplanung gelegt werden. Eine konsequente Aufklärung über möglichen Organerhalt und dessen Konsequenzen ist erforderlich. Nach klinischer Untersuchung und histologischer Sicherung des Befundes sollte in fast allen Fällen organerhaltendes stadienadaptiertes OP-Verfahren genutzt werden. Intraoperativ ist einer Sicherung tumorfreier Schnittränder mittels Schnellschnittuntersuchung anzustreben. Eine psychoonkologische Mitbetreuung soll allen Patienten angeboten werden.

Eine Zentralisierung der Therapie erscheint aufgrund der exzellenten Ergebnisse in
englischen wie niederländischen Zentren auch für Deutschland unbedingt wünschenswert. Bis
dahin kann in Anlehnung an die sehr guten Erfahrungen des Zweitmeinungsnetzwerks Hodentumor
die Zweitmeinungsplattform eKonsil Urologie (https://www.ekonsil.org) genutzt werden.
Eine Applikation für die rheumatologische Versorgung:
RheCORD
Authors: Welcker Martin , Klennert Michael , Aries Peer , Bartz-Bazzanella Peter , Von der Decken Cay , Engelbrecht Matthias , Gauler Georg , Hornig Johannes , Karberg Kirsten , Kuhn Christoph , Schuch Florian , Späthling-Mestekemper Susanna , Vorbrüggen Wolfgang , Wurth Patrick , Muth Theresia , Froschauer-Häfele Sonja , Mühlensiepen Felix , Popp Florian , Burigk Kristin , Kladny Heike , Kleinert Stefan
Published: August 2023

Heutzutage haben medizinische Gesundheits-Applikationen (Apps) einen zunehmenden
Stellenwert. Auf nahezu jedem neuen Smartphone sind Gesundheits-Applikationen
installiert. RheCORD, eine medizinische Applikation in der Rheumatologie, wird
im Folgenden beschrieben und im medizinischen Kontext bewertet.
Einsatzmöglichkeiten,Vorteile und Limitationen werden beschrieben.
POINT: Pipeline for Offline Conversion and Integration of Geocodes and Neighborhood Data
Authors: Guo Kevin , McCoy Allison B. , Reese Thomas J. , Wright Adam , Rosenbloom Samuel Trent , Liu Siru , Russo Elise M. , Steitz Bryan D.
Published: August 2023

Objectives Geocoding, the process of converting addresses into precise geographic coordinates, allows researchers and health systems to obtain neighborhood-level estimates of social determinants of health. This information supports opportunities to personalize care and interventions for individual patients based on the environments where they live. We developed an integrated offline geocoding pipeline to streamline the process of obtaining address-based variables, which can be integrated into existing data processing pipelines.

Methods POINT is a web-based, containerized, application for geocoding addresses that can be deployed offline and made available to multiple users across an organization. Our application supports use through both a graphical user interface and application programming interface to query geographic variables, by census tract, without exposing sensitive patient data. We evaluated our application's performance using two datasets: one consisting of 1 million nationally representative addresses sampled from Open Addresses, and the other consisting of 3,096 previously geocoded patient addresses.

Results A total of 99.4 and 99.8% of addresses in the Open Addresses and patient addresses datasets, respectively, were geocoded successfully. Census tract assignment was concordant with reference in greater than 90% of addresses for both datasets. Among successful geocodes, median (interquartile range) distances from reference coordinates were 52.5 (26.5–119.4) and 14.5 (10.9–24.6) m for the two datasets.

Conclusion POINT successfully geocodes more addresses and yields similar accuracy to existing solutions, including the U.S. Census Bureau's official geocoder. Addresses are considered protected health information and cannot be shared with common online geocoding services. POINT is an offline solution that enables scalability to multiple users and integrates downstream mapping to neighborhood-level variables with a pipeline that allows users to incorporate additional datasets as they become available. As health systems and researchers continue to explore and improve health equity, it is essential to quickly and accurately obtain neighborhood variables in a Health Insurance Portability and Accountability Act (HIPAA)-compliant way.
Association Between Diabetes and Personality Traits Among the Elderly
in China: A Latent Class Analysis
Authors: Xiong Peisheng , Ye Wanbao , Xiong Meijuan , Chen Kangkang , Xu Kai
Published: August 2023

Background The present study aimed to identify individuals with different
personalities using latent class analysis and further distinguish those with a
high risk of diabetes among different clusters.

Methods Data were utilized from a large-scale, cross-sectional
epidemiological survey conducted in 2018 across 23 provinces in China, employing
a multi-stage, stratified sampling technique. Latent class cluster analysis was
performed to identify distinct personality clusters based on a series of
variables concerning life attitudes. Logistic regression was used to calculate
adjusted odds ratios (AORs) after controlling for potential confounding
variables, including age, gender, body mass index, smoking status, alcohol
consumption, hypertension, and physical activity levels, to determine the
association between these groups and diabetes.

Results Four distinct personality clusters were identified, namely the
energy-poor (2.0%), self-domination (61.3%), optimistic
(21.3%), and irritable (15.4%) groups. The prevalence of
diabetes in these groups was 14.6%, 9.7%, 9.3%, and
11.6%, respectively. After adjusting for potential confounders, the
“energy-poor group” exhibited more odds of having diabetes as
compared to the “optimistic group” (AOR 1.683, 95%CI:
1.052–2.693; P=0.030).

Conclusion This study identified an energy-poor group of individuals with
a high risk of diabetes. Targeted interventions should consider the emotional
and personality characteristics of the elderly.
Palliative Care: From Global to Local Needs
Authors: Gómez García Wendy Cristhyna , Torres Núñez Marleni Regalada
Published: August 2023

Palliative care (PC) is a comprehensive approach that focuses on improving the quality of life of patients and families that face fatal diseases by optimal minimization of suffering. Seventy-eight percent of patients who benefit from palliative support live in low-and-middle-income countries, where the access to these services is limited. Six percent of the patients are below the age of 15. The aim of this study is to review briefly the history of PC and its global challenges and indicate its impact and barriers in the Dominican Republic. A literature review in PubMed and analysis of the history of impact globally of PC and a remark of Dominican Republic local program. Some of the identifiable barriers are the limited support from authorities and health systems, the discomfort of healthcare staff in providing PC, the lack of knowledge, as well as experience, and team support. Not only do low-and-middle-income countries face these challenges, but also globally there is an urgency of the integration of PC services to the different healthcare systems to improve quality of life. This was experienced in the Dominican Republic when the first PC program started in 2012. Currently, local efforts are being made to increase the impact of the program and to make it accessible to more patients and families.
Comparative Evaluation of Postoperative Pain Scores and Opioid Consumption in Septorhinoplasty After Administration of Single-Dose Preemptive Paracetamol and Ibuprofen: A Randomized Controlled Trial
Authors: Alshehri Ali Abdullah
Published: August 2023

Introduction Septorhinoplasty operates on the nose's bone and cartilage and is ensued by severe postoperative pain.

Objective The objective of this study is to evaluate the effects of preoperative administration of intravenous (IV) paracetamol and ibuprofen on postoperative pain scores in patients undergoing septorhinoplasty.

Methods A total of 150 patients undergoing septorhinoplasty were randomly assigned into 3 groups with 50 patients in each group. The control group (group A) was administered 100 ml saline solution; the paracetamol group (group B) was administered 1,000 mg of IV paracetamol in 100 ml of saline solution; and the ibuprofen group (group C) was administered 800 mg of IV ibuprofen in 100 ml of saline solution before surgery. Opioid analgesics were employed to achieve postoperative analgesia. Postoperative pain was evaluated using the visual analogue scale (VAS). Postoperative opioid consumption and adverse effects were also recorded for each patient.

Results In comparison with group A, the score in the VAS of groups B and C was statistically lower in all the time intervals (p < 0.05). In the 1st and 6th hours postoperatively, group C's score in the VAS in was lower than that of group B (p < 0.05). In the control group, total opioid consumption was highest in all time intervals (p < 0.05). In group C, total opioid consumption was significantly lower than in group B in the 0 to 6 and 6 to 12 hours intervals. (p < 0.05).

Conclusion The single-dose preemptive administration of ibuprofen has a more profound postoperative analgesic effect than paracetamol in the first 6 hours after septorhinoplasty. After the first 6 hours postsurgery, there is no difference between ibuprofen and paracetamol in terms of analgesic effect.
Multidisciplinary Cognitive Function Assessment of Good versus Poor Performance in Children with Cochlear Implants: An Observational Cross-Sectional Study
Authors: Ibraheem Ola A. , Abdelghani Mohamed , Hassan Elham M. , El-Nebtity Nadia , Gad Nahlah H.
Published: August 2023

Introduction Despite the developing technology of cochlear implants (CIs), implanted prelingual hearing-impaired children exhibit variable speech processing outcomes. When these children match in personal and implant-related criteria, the CI outcome variability could be related to higher-order cognitive impairment.

Objectives To evaluate different domains of cognitive function in good versus poor CI performers using a multidisciplinary approach and to find the relationship between these functions and different levels of speech processing.

Methods This observational, cross-sectional study used the word recognition score (WRS) test to categorize 40 children with CIs into 20 good (WRS/65%) and 20 poor performers (WRS < 65%). All participants were examined for speech processing at different levels (auditory processing and spoken language) and cognitive functioning using (1) verbal tests (verbal component of Stanford-Binet intelligence [SBIS], auditory memory, auditory vigilance, and P300); and (2) performance tasks (performance components of SBIS, and trail making test).

Results The outcomes of speech processing at different functional levels and both domains of cognitive function were analyzed and correlated.

Speech processing was impaired significantly in poor CI performers. This group also showed a significant cognitive function deficit, in which the verbal abilities were more affected (in 93.5%) than in the good performers (in 69.5%). Moreover, cognitive function revealed a significant correlation and predictive effect on the CI speech outcomes.

Conclusion Cognitive function impairment represented an important factor that underlies the variable speech proficiency in cochlear-implanted children. A multidisciplinary evaluation of cognitive function would provide a comprehensive overview to improve training strategies.
A Cross-Sectional Study of Unlocking Childhood Cancer Services during COVID-19 Pandemic: A Pediatric Oncology Tertiary Care Center's Experience from a Developing Country
Authors: Sneha Latha M. , Scott Julius Xavier , Kancharla Adarsh , Jayraman Dhaarani , Kothandan Balaji Thiruvengadam , Koneru Shree Hasitha
Published: August 2023

Introduction The global coronavirus disease 2019 (COVID-19) pandemic has made the provision of cancer care services a challenging task all over the world, even in developed countries. Multiple studies have already reported increased rate of diagnostic delays, interruptions in radiotherapy and chemotherapy administration, and shortage of health care personnel to deliver these services.

Objective The aim of this study was to analyze the impact of strategies used to deliver uninterrupted childhood cancer services at our center during the COVID-19 pandemic.

Materials and Methods This is a cross-sectional study of the children less than 18 years of age admitted at our center between March 2020 and September 2021 to assess the effect of strategies adopted to provide uninterrupted cancer services during the COVID-19 pandemic. All the children with cancer who were managed during the study period were included in the study. The children who had treatment interruptions/lost to follow-up prior to onset of COVID-19 were excluded from the study. The primary outcome was to measure the effect of COVID-19 on delivery of cancer care services. The secondary outcome was to assess whether the strategies followed at our center helped to reduce diagnostic delays or loss to follow-up during the COVID-19 pandemic.

Results Out of total 1,490 admissions, 199 children were managed during the study period. Among the 199 children managed, 124 of them were newly diagnosed, 75 had ongoing treatment, 16 children relapsed, 13 children received palliative care, and 6 families were lost to follow-up. Out of 1,471 tests done, only 16 children and 6 caregivers tested COVID-19 positive during routine screening. Thirty-five underwent surgery and 23 received radiotherapy during this period. Among 199 children, 143 (71.8%) received financial support for hospital expenses, 23 (11.5%) received travel support, 20 (10%) were provided free accommodation, and 15 (7.5%) received home delivery of oral chemotherapy and pain medications. A total of $86,989.05 was supported for diagnostic investigations, COVID-19 testing, chemotherapy, and supportive care; $1,144.90 for travel support; and $17,010.94 was waived off by hospital administration to support the poor families.

Conclusion The shared care model, support from nongovernmental organizations and hospital administration, and utilization of local resources productively and effectively helped to avoid diagnostic delays and treatment interruptions, and provide uninterrupted pediatric cancer care services at our center.
Advances in perfusion propel 3D in vitro tissue models to new applications
Authors: Liebendorfer Adam
Published: August 2023

Emerging microfluidic devices allow researchers to mimic the vasculature of real tissues with increasing accuracy.
Controllable phase modulation and electronic structures of monolayer MoSe2xTe2(1−x) alloys grown via molecular beam epitaxy
Authors: Yang Ming , Tong Qunchao , Yu Yayun , Liu Peng , Wang Guang , Dai Jiayu
Published: August 2023

Controllable phase modulation and electronic structure are essential factors in the study of two-dimensional transition metal dichalcogenides due to their impact on intriguing physical properties and versatile optoelectronic applications. Here, we report the phase-controlled growth of ternary monolayer MoSe2xTe2(1−x) (0 ≤ x ≤ 1) alloys induced through in situ doping and composition tuning via molecular beam epitaxy. Our approach leverages the substitution of selenium for tellurium to lower the energy barrier of the semi-conducting 2H and semi-metallic 1T′ phase transition. The alloys’ lattice constants, Mo-3d binding energy and electronic bandgap were demonstrated to be tunable by varying the selenium composition (x), respectively. First-principles calculations agree well with our experimental results, revealing that the valence band bowing effect of the monolayer alloys is attributed to the difference in coupling between anions and cations. This work provides a new pathway for phase modulation growth and controllable electronic structure of ternary monolayer transition metal dichalcogenide alloys, which is of great significance for ohmic contact and band engineering in developing transistor device applications using two-dimensional semiconductors.
Can you amuse the audience through an interpreter?
Authors: Bartłomiejczyk Magdalena
Published: August 2023

In this article, I investigate how interpreters handle humorous utterances during plenary debates of the European Parliament, focusing on the input by one Polish Member of the European Parliament (MEP), Janusz Korwin-Mikke. The source speeches (in Polish or English) are analysed bottom-up to identify the types of humour favoured by the speaker. The most frequent ones are irony, ad hominem arguments with an element of ridicule, absurdity, and shifts in register. Subsequently, a pragmatically oriented comparative analysis is conducted to assess whether and how individual instances of humour are transferred by interpreters. Additionally, possible side effects are considered, such as shifts accompanying transferred humour and message incoherence resulting from humour loss. Register humour is typically removed by interpreters. The successful handling of absurdity relies mainly on compression and often fails, while ad hominem and irony appear to be relatively less challenging to interpret. Interestingly, irony is occasionally added by interpreters, either to boost the speaker’s comical intent or to distance themselves from his views.
Effects of density on the strength of sexual selection in the laboratory and in nature
Authors: Cothran Rickey D , Schmidenberg David , Stiff Andy R , Wellborn Gary A , Relyea Rick A
Published: August 2023

There is a growing effort to understand how sexual selection varies over space and time under different ecological conditions and how this can maintain variation in sexual traits. An interesting ecological condition is population density, which can either increase or decrease sexual selection depending on the natural history of the species. We examined sexual and natural selection in an undescribed amphipod species (Hyalella sp.) using surveys of two natural populations that increase in density from spring to summer. We also conducted an experiment that directly manipulated density to assess the effects on sexual selection. In the field during spring (low density) and summer (high density), we documented sexual selection on male traits, including body size, gnathopods and antennae. We found that the magnitude and direction of this selection changed from spring to summer and that selection patterns differed between populations. In the experiment, we found no sexual selection occurred at low density, but found significant positive selection on all three male traits at medium and high densities. These results underline the importance of isolating individual ecological factors to determine their role in sexual selection while also documenting patterns in natural populations to understand how selection varies over space and time.
Thiazolidinediones: Recent Development in Analytical Methodologies
Authors: Patel Tarang , Patel Vatsal
Published: August 2023

The instrumental analytical methods that have been developed and utilized for the determination of thiazolidinedione in bulk medications, formulations and biological fluids have been reviewed after an in-depth analysis of the literature published in a variety of analytical and pharmaceutical chemistry-related journals. The approaches covered by this research, which covers the years 2001–2022, include complex methods for analysis, chromatographic techniques and spectrometric analytical procedures. The mobile phase, flow rate, sample matrix, wavelength and other factors identified in the literature were just a few of the parameters used to evaluate thiazolidinediones. The present review focuses on the published analytical techniques for thiazolidinedione analysis that have been previously identified in the literature. The specified outcomes followed extensive learning, and the most recent advances in analytical methods for the identification of pioglitazone, pioglitazone HCl, rosiglitazone, rosiglitazone maleate and lobeglitazone were reviewed. Additionally, this article briefly discusses features of analytical discovery on thiazolidinediones, which will enable readers to access all discoveries in one place with precise outcomes.
Analysis of the Epidemiological Features and Treatment Results of Burn Injuries in a Burn Center in Turkey
Authors: Erdogan Hünkar , Sencan Arzu
Published: August 2023

The aim of the study was to reveal the epidemiological characteristics and clinical course of burn patients who were hospitalized in our burn center between 2015 and 2020 and to compare the results between nationalities. The data were retrospectively evaluated in terms of age, gender, time of admission, the total body surface area burned, the degree of burn, the accident location, the presence of wound infection, surgical intervention, length of hospital stay, mortality, educational status of the parents, and nationality; 59.8% of 1496 cases were male, mean age was 40.38 months. The most common age range was 0-2 years. 78.4% were admitted within the first 24 hours; 50.5% of the admissions were from İzmir and its districts. Burn trauma most commonly occurred indoors in all age groups. The most common cause was scalding. Isolation of microorganism in wound cultures was most commonly detected in second degree burns. The most common infection agent was Pseudomonas aeruginosa. The surgical intervention rate was 19%. The mean length of hospitalization was 14.46 ± 12.17 days. Total burned surface, hospitalization time, the infection, and mortality rate were higher in patients who underwent surgical intervention. Parents were mostly primary school graduates. 11.6% of the patients were of foreign nationality. No significant difference was found in the analyzed parameters between nationalities. In conclusion; burn trauma is most commonly seen in the 0-2 age group, regardless of parental education levels. Therefore, it is of great importance to provide training on burns to families and those responsible for the care of children.
Surgical Casualty Care in Contested Distributed Maritime Operations: Lessons Learned From the Falklands War
Authors: Hughey Scott , Cole Jacob , Brust Adam , Checchi Kyle , Kotler Joshua , Lin Andrew
Published: August 2023

The Falklands Campaign was fought a significant distance from the home base of the British Fleet. The planning and delivery of medical care during this campaign can provide significant lessons for strategic medical planning in other far spread geographic locations, including the Indo-Pacific region. Consideration of doctrine, including Role 1-4 facilities and the golden hour, may need to be reconsidered in light of changing scenarios. New concepts such as the “90-in-90” and “3-in-3” are also discussed as a framework for future planning in the U.S. Indo-Pacific Command area of responsibility.
BSBM-09 IN VIVO CRISPR ACTIVATION SCREEN IDENTIFIES ß-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 (BACE1) AS A DRIVER OF NON-SMALL CELL LUNG CANCER BRAIN METASTASIS
Authors: Chafe Shawn , Zhai Kui , Aghaei Nikoo , Miletic Petar , Brown Kevin , Mobilio Daniel , Venugopal Chitra , Kieliszek Agata , Hynds Robert , Lam Fred , Moffat Jason , Swanton Charles , Bao Shideng , Singh Sheila
Published: August 2023

Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumour and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome wide CRISPR activation (CRISPRa) screen to identify molecular drivers of brain metastasis from a NSCLC patient-derived xenograft model. We identified activation of the Alzheimer’s disease associated ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) led to a significant increase in brain metastasis. BACE1 is highly expressed in NSCLC and patients with BACE1 expressed in their metastatic brain tumour survived for shorter periods. Genetic loss with CRISPR-Cas9 or pharmacological inhibition of BACE1 with MK-8931 decreased cell proliferation and sphere forming capacity in vitro. Furthermore, BACE1 knockout and MK-8931 treatment blocked brain metastasis in vivo. Mechanistically, we identified BACE1 activation lead to downstream signalling through MEK and ERK. Together our data highlights the power of in vivo CRISPR screening to identify novel molecular drivers and potential therapeutic targets of NSCLC brain metastasis.
BSBM-17 NOVEL VALIDATED PATIENT-DERIVED MODELS OF A RECTAL CANCER BRAIN METASTASIS
Authors: Barros Guinle Maria Isabel , Tran Caitlynn To-Dyuen , Nasajpour Emon , Xing Yao Lulu , Nakano Michitaka , Nair Indu , Sathe Anuja , Nirschl Jeffrey , Granucci Monica , Prolo Laura M , Ji Hanlee P , Vogel Hannes , Lim Michael , Hayden-Gephart Melanie , Kuo Calvin , Petritsch Claudia K
Published: August 2023

Colorectal adenocarcinomas (CRC) rarely metastasize to the brain, however, survival rates in patients with colorectal brain metastases (CBM) are short, with a median survival of only 4 months from diagnosis. Currently, no evidence-based treatment options against these rare brain metastases are available (PMC). Therefore, characterization of these tumors and development of targeted therapies are imperative.

Optimal models for neoplasms heighten the notoriously low success rate of bench-to-bedside translation. Historically, brain cancer metastases models are established cell lines grown on plastic and transplanted as xenografts (Valiente; PMC7572582). Genomic drift, lack of genetic accuracy and heterogeneity, caused by serial passaging on plastic and in high-serum media, are frequent limitations of these models. Growth in defined media without serum and as 3-dimensional (3-D) spheroids or organoids is thought to improve the fidelity of cancer cell lines (Lee; PMID:16697959; Lo; PMC820864). Despite significant efforts of large collaborative projects (https://hcmi-searchable-catalog.nci.nih.gov/), 3-D rectal brain cancer metastasis models have not been reported.

To address this unmet medical need, we developed 3-D (suspension, organoid) cultures of a rectal adenocarcinoma brain metastasis with moderate to focally poor differentiation. Next-generation sequencing, expression profiling, and immunohistochemistry were performed to validate our models. Our data confirmed that the PDO model contains tumor cells; pathogenic alterations and expression profiles in the models largely match that of the original tumor. Overall, we detected a significant phenotypic overlap with the original tumor sample. Spatial profiling and PDO-derived xenografts are in progress and will facilitate experimental therapeutics. Taken together, our models retained tumor heterogeneity and fidelity from the primary tumor, making this one of the first studies to establish 3-D patient-derived models for disease progression in rectal cancer brain metastases. Collectively, these models will be valuable translational tools for future exploration of targeted therapy, which remains absent in this disease process.
BSBM-19 CROSS-PRESENTATION BY TUMOR-ASSOCIATED MACROPHAGES MEDIATES THE TRANSITION FROM PROGENITOR TO TERMINAL T CELL EXHAUSTION IN PRIMARY AND METASTATIC BRAIN TUMORS
Authors: Polania Jessica Waibl , Hoyt-Miggelbrink Alexandra , Tomaszweski William , Wachsmuth Luke , Lorrey Selena , Fecci Peter
Published: August 2023

Glioblastoma (GBM) and brain metastases remain largely resistant to immunotherapeutic intervention. T cell exhaustion, a differentiation state characterized by loss of function and persistence, contributes to this resistance. Two exhaustion subsets, progenitor (Tex_prog) and terminal (Tex_term), have been identified, where only Tex_prog remain responsive to immunotherapy. To date, the dynamics and characteristics of these exhausted populations in GBM and brain metastases remain unclear. Herein, we identify a striking loss of Tex_prog in a murine model of GBM throughout tumor progression. We elucidate the requirements for Tex_prog to Tex_term transition through characterization of T cell exhaustion progression at the RNA (paired scRNA and TCR sequencing) and protein level (flow-cytometry). Tex_prog are enriched for pathways of migration, cell-cell adhesion, and differentiation, whereas Tex_term primarily upregulate cytotoxic pathways. TCRseq revealed that clonal expansion is concentrated to the Tex_term cluster, suggesting a link between Tex_prog transition and proliferation in response to antigen. Likewise, we defined the necessity of hematopoietic antigen presentation, but not tumor-derived antigen presentation for the Tex_prog to Tex_term transition. Of the antigen presenting cells in the TME, tumor-associated macrophages (TAM) had the greatest expression of tumor-antigen loaded MHC I, illustrating their capacity to cross-present. By depleting TAM, we observed disruption of the Tex_prog transition. Similar results were seen in subcutaneous and intracranial melanoma, highlighting the role of TAM in this process across tumor histology and location. Lastly, we identified additional inflammatory cell-cell interactions between T cells and TAM in mice and humans that may contribute to this phenomenon. Taken together, we define T cell exhaustion dynamics in models of primary and metastatic brain tumors, where tumor-antigen presentation by TAM is a critical mediator of the loss of Tex_prog. We extend these findings to human data to better define these complex interactions, which we aim to leverage to overcome immunotherapy resistance.
BSBM-20 INVESTIGATING THE ROLE OF OXIDATIVE PHOSPHORYLATION (OXPHOS) IN CD4+ T CELL ACTIVATION AND RESPONSE TO ANTI-PD1/ANTI-LAG3 IMMUNOTHERAPY IN MELANOMA BRAIN METASTASIS (MBM)
Authors: Guerrieri Renato , Cortez Jacob , Liu Alice , Jeong Kate-Yeonjae , Knighton Barbara , Ferguson Sherise , Davies Michael
Published: August 2023

Brain metastasis is a frequent and deadly complication of metastatic melanoma. While extracranial metastases (ECMs) are often treatable, MBMs remain a critical treatment (tx) challenge to overcome. We previously showed that MBMs are characterized by increased utilization of OXPHOS compared to ECMs, and OXPHOS inhibition increased expression of immune activation transcriptional signatures in MBMs. Thus, we tested the role of tumor OXPHOS on the immune microenvironment and checkpoint immunotherapy response in a syngeneic mouse model with concurrent intracranial (ICr) and subcutaneous (SQ) tumors. Selective OXPHOS inhibition was achieved via CRISPR-KO of Ndufs4 (mitochondrial complex I) in B16-F10 cells and confirmed via Seahorse Analyzer MitoStress Test. Multiplex cytokine analysis of culture supernatant revealed that NDUFS4 KO increased anti-tumor cytokines IFNγ (p=0.016) and IL-2 (p=0.023) and decreased pro-tumor chemokine CXCL2 (p<0.001). Next, we implanted concurrent ICr and SQ B16-F10 tumors in C57BL/6J mice. Flow cytometry demonstrated decreased CD4+ and CD8+ T cell infiltration of ICr versus SQ tumors in both B16-F10 and NDUFS4 KO tumors (all p<0.001). NDUFS4 KO increased total CD4+ T cells (p=0.041) and activated CD4+ T cells (p<0.001) in ICr tumors. Finally, we tested the efficacy of tx with combination anti-PD1/anti-LAG3 (200μg/100μg intraperitoneal 3x/week) versus isotype controls (Ctrl) in these mice. Compared to Wildtype (WT) tumors with Ctrl tx, we observed improved overall survival (OS) in mice with NDUFS4 KO tumors + Ctrl (HR 0.117; p=0.015), WT tumors + anti-PD1/anti-LAG3 (HR 0.071; p=0.005), and NDUFS4 KO tumors + anti-PD1/anti-LAG3 (HR 0.049; p=0.002). For anti-PD1/anti-LAG3 tx, there was a trend for improved OS with NDUFS4 KO versus WT tumors (HR 0.317; p=0.130). Together, these data implicate tumor OXPHOS in CD4+ T cell immunosuppression and a potential target to enhance response to checkpoint immunotherapy in MBMs.
BSLD-06 UNVEILING THE RE-PROGRAMMING OF CHOROID PLEXUS AND LEPTOMENINGEAL METASTASIS
Authors: Nobre Ana Rita , Wang Helen , Estrera Rachel , Boire Adrienne
Published: August 2023

Leptomeningeal metastasis (LM) is an increasingly common, fatal complication of breast and lung cancer. Despite aggressive treatment, neurologic deficits accumulate rapidly, and patients generally succumb to LM within months. We must expand our limited mechanistic knowledge of this disease. Under homeostatic conditions, choroid plexus (ChP), highly vascularized structures within the brain ventricles, restrict the entry of macromolecules and cells into the leptomeninges; however, select cancer cells can cross this barrier and grow within the leptomeningeal space. We hypothesize that interactions between cancer and ChP niche cells alter both the niche and the cancer cells, ultimately supporting LM. During neurogenesis, the ChP display substantial extracellular matrix (ECM) remodeling, which is elegantly modulated by dynamic spatiotemporal regulation of MMPs, Wnt signaling, among other effector proteins. Similarly, 2-photon imaging of ChP collected from mice harboring LM revealed a profound ECM remodeling of the ChP when compared with naïve mice. This remodeling was accompanied by increased levels of MMP2 and MMP9 in the CSF. Furthermore, single-cell-RNA-sequencing of ChP reveals that Wnt is the top differentially expressed pathway in metastatic ChP in comparison with normal ChP, supporting a role for developmental signaling within the ChP in LM. Interestingly, SPARC, a major ECM modulator in tissue repair and an essential component of the stem cell niche chemoattractant factors secreted by the subventricular zone (SVZ), is enriched in metastatic mouse ChP suggesting that SVZ- and ChP-secreted signals are key in LM progression. The use of clinically-annotated human samples and mouse models of LM, and the integration of transcriptomics and proteomics enabled us to identify key signaling pathways, and capture the re-programming of ChP niche and cancer cells that unlock the leptomeningeal space to cancer cells. The timeframe for this evolution will be further revealed by analysis of mouse and human samples at different stages of cancer progression.
CLRM-03 THE TENTATIVE APPLICATION OF EN BLOC CONCEPT IN THE PEDIATRIC BRAIN TUMOR: EXPERIENCE FROM A LARGE PEDIATRIC CENTER IN CHINA
Authors: Ma Jie
Published: August 2023

BACKGROUND

The less allowable blood loss and tolerance of intraoperative blood loss of children lead to the high rate of massive blood transfusion. The surgical concepts of en bloc resection may contribute to the improvement of brain tumor resection.

OBJECTIVE

To investigate the effects of en bloc concept on short outcomes of pediatric brain tumors and factors associated with the application of en bloc concept.

METHODS

According to the surgical concept involved, the patients were divided into three subgroups-complete en bloc concept, partial en bloc concept and piecemeal concept. The matching-comparison(en bloc group consisting of the first two subgroups and piecemeal group) was conducted to investigate the effect of the en bloc concept on the short-term outcomes. Then the patient data after January 2018, when the en bloc concept was routinely integrated into brain tumor surgery in our medical center, were reviewed and analyzed to find out the predictors associated with the application of en bloc concept.

RESULTS

In the en bloc group, the perioperative outcomes, including hospital stay(p=0.001), PICU stay(p=0.003), total blood loss(p=0.015), transfusion rate(p=0.005) and complication rate(p=0.039), were all significantly improved. The multinomial logistic regression analysis showed that tumor volume, bottom vessel, and imaging features, like encasing nerve or pass-by vessel, finger-like attachment, ratio of “limited line” and ratio of “clear line” remained independent predictors for the application of en bloc concept in our medical center.

CONCLUSION

The application of en bloc concept based on the imaging features can improve the short-term outcomes.
LMAP-17 FEASIBILITY OF COGNITIVE-SPARING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: INITIAL REPORT OF PHASE II COG-SRS TRIAL
Authors: Hopper Austin , Connor Michael , Karunamuni Roshan , Sanghvi Parag , Kim Grace , Bruggeman Andrew , Moiseenko Vitali , Farid Nikdokht , McDonald Carrie , Hattangadi-Gluth Jona
Published: August 2023

Radiotherapy at high doses leads to white matter (WM) and hippocampal injury which can cause cognitive decline. We designed the first, to our knowledge, evidence-based cognitive-sparing brain SRS trial for patients with limited brain metastases. In this report we analyze feasibility of cognitive-sparing SRS, utilizing dose constraints for eloquent WM tracts and bilateral hippocampi. Patients underwent high-resolution quantitative diffusion and volumetric MRI at baseline and post-SRS follow-up. Comprehensive neurocognitive assessment was performed at baseline and 3 months post-SRS evaluating multiple neurocognitive domains. Clinical workflow was largely automated with robust, validated segmentation of eloquent WM tracts and the hippocampi. Single fraction max dose constraints to WM tracts and hippocampi were 12 Gy and 8.4 Gy, respectively, with 3 and 5 fraction equivalent doses based on our prior NTCP studies. Patient accrual, follow-up imaging and neurocognitive testing is still active. To date, 59 patients and 114 lesions have been treated with cognitive-sparing linac-based SRS on trial. Median age is 63 years. Patients had 1-4 brain metastases; median prescription dose was 24Gy/1, 27Gy/3, or 30Gy/5 depending on target volume. Most patients were treated <7 business days from MRI. Cognitive endpoints have been collected on 89.5% of patients. Cognitive-sparing constraints were met in 79.3% of plans while maintaining standard clinical SRS plan indices and coverage benchmarks. Plans going over constraints had tumors overlying or within 1 mm of eloquent ROIs. Local control for treated lesions at 6 months was 97.9% and 95.7% at 12 months. Distant intracranial control was 68.1% at 6 and 12 months. Median OS was 18 months. Cognitive-sparing SRS treatment planning was successfully implemented for the majority of treated lesions with excellent local control. Mitigation of damage to eloquent structures has potential to further reduce cognitive decline after SRS. Full neurocognitive outcomes will be reported after accrual and testing are complete.
NEIM-02 CHARACTERIZATION OF LARGE BRAIN METASTASES WITH18F-FLUCICLOVINE PET/CT TREATED WITH STAGED STEREOTACTIC RADIOSURGERY (SSRS): INTERIM ANALYSIS OF A PILOT STUDY
Authors: Rosa Alonso La , Chundru Surya , Vuong Hao , Tom Martin , Kutuk Tugce , Wieczorek D Jay , Lee Yongsook , Avendano Maria Carolina , Rubens Muni , Tolakanahalli Ranjini , McDermott Michael , Hall Matthew , Gutierrez Alonso , Ahluwalia Manmeet , Mehta Minesh , Kotecha Rupesh
Published: August 2023

We report the interim analysis of a phase 1, proof-of-concept study (NCT04689048), to assess the potential clinical utility of an amino acid radiotracer, 18F-fluciclovine PET/CT, as a functional integral biomarker for previously untreated patients with large brain metastases [BM] (≥1 lesion; >2cm) treated with staged stereotactic radiosurgery (SSRS). We reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection for the first seven enrolled patients (9 lesions) who completed baseline imaging, and five patients (7 lesions) who completed the treatment course (SSRS). Patients underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI before 1st SSRS (15 Gy), repeated after 4 weeks (interim; before 2nd SSRS [15 Gy]), and 8 weeks after treatment completion (first follow-up after 2nd SSRS). The median age was 72 years and 57% were female. All lesions exhibited baseline increased 18F-fluciclovine uptake compared to normal contralateral brain. The median baseline lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative changes in diameter and volume were both -2% (-23% to +13% and -60% to +30%, respectively) at the interim scans, and -30% (-44% to +0.2%) and -43% (-94% to +13%), respectively, at first follow-up. Corresponding median relative changes values for SUVmax, SUVpeak, and SUVmean at interim scan were -20% (-73% to +174%), -9% (-75% to +99%), and -14% (-69% to +36%), and at first follow-up -59% (-87% to -21%), -41% (-86% to +11%), and -21% (-79% to +44%), respectively. In conclusion, this proof-of-concept interim study reports 18F-fluciclovine metrics for patients with large BMs, demonstrating interval reduction in PET metrics after SSRS, more than anatomical measurements alone, highlighting the potential of this as an imaging biomarker.
NEIM-15 AN EXCEPTION TO THE METASTATIC RULE: A NON-ENHANCING MIDBRAIN LESION DUE TO METASTATIC FIBROMYXOID SARCOMA WITH EXTENSIVEINFLAMMATORY INFILTRATE
Authors: Rogawski David , Wheeler Josh , Nie Esther , Zhu William , Villanueva Eleanor , Coffey Gwen , Ganjoo Kristen , Fischbein Nancy , Iv Michael , Vogel Hannes , Nagpal Seema
Published: August 2023

Metastases from extra-CNS sites typically enhance on MR after the administration of gadolinium-based contrast agents due to disruption of the blood-brain barrier. Fibromyxoid sarcoma involving the brain is extremely rare, with only a few reported cases manifesting as well-circumscribed enhancing masses. Here, we report an extremely rare non-enhancing brain metastasis secondary to an already rare sarcoma. A 44-year-old woman with gluteal fibromyxoid sarcoma metastatic to cervical paraspinal muscles and adrenal gland treated with ipilimumab/nivolumab presented with diplopia and was found to have an 8 mm T2-hyperintense midbrain lesion without enhancement or mass effect. An inflammatory etiology associated with checkpoint inhibitor therapy was suspected, and she was treated with IV methylprednisolone 1 g daily for 3 days followed by an oral prednisone taper, IV immunoglobulin, and plasma exchange without improvement. The midbrain lesion steadily grew over 15 months of follow up, eventually involving the bilateral medial thalami and demonstrating diffusion restriction in the midbrain, but never showing gadolinium enhancement. The imaging was reminiscent of peripheral brainstem non-enhancing band-like lesions reported in leptomeningeal lung cancer, however CSF cytology was repeatedly normal, as was extensive infectious and inflammatory testing. Her neurologic disability continued to progress, with development of bilateral oculomotor nerve palsies, dysarthria, and depressed level of alertness, devolving into non-convulsive status epilepticus requiring intubation. She died six months after onset of neurologic symptoms. At autopsy, histologic and immunohistochemical evaluation revealed fibromyxoid sarcoma (MUC-4 positive, TAOK1-FUS fusion) centered on the periventricular aqueduct with accompanying disseminated single-cell infiltration throughout the midbrain. The background midbrain and periventricular parenchyma were notable for voluminous microglial activation and histiocytic infiltrate. In sum, this case represents a radiographically unique sarcoma brain metastasis which on pathologic exam showed robust inflammatory changes far out of proportion to the tumor present.