bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance response of increasing the standardized ileal digestible tryptophan:lysine ratio in diets containing 40% dried distiller grains with solubles
Authors: Clizer David A , Tostenson Blair J , Frederick Brent , Cline Paul M , Samuel Ryan S
Published: August 2023

A total of 1,170 pigs (PIC 800 × PIC, initially 38.6 kg) were used in a 98-d grow-finish study to determine the performance response of pigs fed increasing levels standardized ileal digestible (SID) Trp:Lys ratio in diets containing 40% dried distillers grains with solubles (DDGS). Five dietary treatments were fed and consisted of a corn-soybean meal (SBM) diet or diets containing 40% DDGS with SID Trp:Lys ratios of 15%, 18%, 21%, or 24%. Each treatment was replicated 9 times and pens contained 26 pigs with the equal number of gilts and barrows. Data was analyzed as a randomized complete block design with previous nursery treatment as a random blocking factor. Pair-wise comparisons were used to evaluate the impact of diets on performance and carcass traits; specifically to compare the corn-SBM dietary treatment against other dietary treatments. Single degree of freedom orthogonal polynomials were used to evaluate the dose–response of increasing the SID Trp:Lys ratio in 40% DDGS diets. Increasing the SID Trp:Lys ratio in diets containing 40% DDGS increased (linear, P ≤ 0.02) average daily gain (ADG), average daily feed intake (ADFI), final body weight (BW), hot carcass weight (HCW), carcass gain, and daily carcass gain. Increasing the SID Trp:Lys ratio in 40% DDGS diets did not impact (P ≥ 0.65) gain to feed (G:F) for the cumulative period. Pigs fed the corn-SBM diet had greater (P ≤ 0.01) ADG and a heavier (P ≤ 0.01) final BW compared to pigs fed 40% DDGS diets, regardless of the SID Trp:Lys ratio. Diets that contained 40% DDGS with a SID Trp:Lys ratio of 24% had no difference (P|t| = 0.25) in ADFI compared to the corn-SBM dietary treatment. The cumulative G:F of pigs did not differ (P = 0.32) between pigs fed corn-SBM diets and diets containing 40% DDGS regardless of the SID Trp:Lys ratio. However, pigs receiving the corn-SBM diets had heavier HCW, greater carcass yields, total carcass gain, and daily carcass gain (P < 0.01) compared to pigs fed the 40% DDGS diets regardless of SID Trp:Lys ratio. In conclusion, increasing the SID Trp:Lys ratio in 40% DDGS diets improved ADG and ADFI for the overall grow-finish period. However, when compared to a corn-SBM diet, increasing the SID Trp:Lys ratio in 40% DDGS diets did not correct the growth performance or carcass characteristics of pigs.
Internal organ dose rate conversion coefficients of Japanese macaques to 134Cs,137Cs and 131I
Authors: Takamura Yuta , Kajimoto Tsuyoshi , Tanaka Kenichi , Yamamoto Tomoya , Suzuki Masatoshi , Inaba Yohei , Chida Koichi , Fukumoto Manabu , Rangacharyulu Chary , Endo Satoru
Published: August 2023

The purpose of this study was to estimate the internal dose of radiation in Japanese macaques (aka Nihonzaru or snow monkey) due to the Fukushima nuclear power plant accident. Images of a male Japanese macaque weighing ~10 kg were acquired using a multi-slice computed tomography (CT) scan with a 64-row segment detector. The CT images were used to create voxel phantoms of the bones, bone marrow, brain, eyes, heart, lungs, stomach, liver, spleen, pancreas, kidneys, intestines, bladder, testes, thyroid and miscellaneous tissue. The Particle and Heavy Ion Transport System (PHITS) Monte Carlo code was used to calculate the internal exposure rate conversion factors for 134Cs, 137Cs and 131I isotopes for the created voxel phantoms with a statistical precision higher than 1%. The PHITS-calculated energy deposits were compared with those for rhesus monkeys. The results showed that the fractions of energy deposits for β-radiation in different organs were almost identical between the two species. For γ-radiation, there was excellent agreement in the self-absorption rate with the approximate curve of the Japanese macaque, with an average deviation of 2%. The maximum deviation of 12% was for the kidney, which has two organs, so the error with the approximate curve is slightly larger due to the energy loss created between organs.
Internal kinematics of Gaia DR3 wide binaries: anomalous behaviour in the low acceleration regime
Authors: Hernandez X
Published: August 2023

The Gaia eDR3 catalogue has recently been used to study statistically the internal kinematics of wide binary populations using relative velocities of the two component stars, ΔV, total binary masses, mB, and separations, s. For s ≳ 0.01 pc, these binaries probe the low-acceleration a ≲ 2a0 regime where gravitational anomalies usually attributed to dark matter are observed in the flat rotation curves of spiral galaxies, where a0 ≈ 1.2 × 10−10 m s−2 is the acceleration scale of MOND. Such experiments test the degree of generality of these anomalies, by exploring the same acceleration regime using independent astronomical systems of vastly smaller mass and size. A signal above Newtonian expectations has been observed when a ≲ 2a0, alternatively interpreted as evidence of a modification of gravity, or as due to kinematic contaminants; undetected stellar components, unbound encounters, or spurious projection effects. Here I take advantage of the enhanced DR3 Gaia catalogue to perform a more rigorous study of the internal kinematics of wide binaries than what has previously been possible. Internally determined Gaia stellar masses and estimates of binary probabilities for each star using spectroscopic information, together with a larger sample of radial velocities, allow for a significant improvement in the analysis and careful exclusion of possible kinematic contaminants. Resulting ΔV scalings accurately tracing Newtonian expectations for the high acceleration regime, but markedly inconsistent with these expectations in the low acceleration one, are obtained. A non-Newtonian low acceleration phenomenology is thus confirmed.
Accretion disc evolution in GRO J1655−40 and LMC X-3 with relativistic and non-relativistic disc models
Authors: Yilmaz Anastasiya , Svoboda Jiří , Grinberg Victoria , Boorman Peter G , Bursa Michal , Dovčiak Michal
Published: August 2023

Black hole X-ray binaries are ideal environments to study the accretion phenomena in strong gravitational potentials. These systems undergo dramatic accretion state transitions and analysis of the X-ray spectra is used to probe the properties of the accretion disc and its evolution. In this work, we present a systematic investigation of ∼1800 spectra obtained by Rossi X-Ray Timing Explorer Proportional Counter Array observations of GRO J1655−40 and LMC X-3 to explore the nature of the accretion disc via non-relativistic and relativistic disc models describing the thermal emission in black hole X-ray binaries. We demonstrate that the non-relativistic modelling throughout an outburst with the phenomenological multicolour disc model DISKBB yields significantly lower and often unphysical inner disc radii and correspondingly higher (∼50–60 per cent) disc temperatures compared to its relativistic counterparts KYNBB and KERRBB. We obtained the dimensionless spin parameters of a* = 0.774 ± 0.069 and a* = 0.752 ± 0.061 for GRO J1655−40 with KERRBB and KYNBB, respectively. We report a spin value of a* = 0.098 ± 0.063 for LMC X-3 using the updated black hole mass of 6.98 M⊙. Both measurements are consistent with the previous studies. Using our results, we highlight the importance of self-consistent modelling of the thermal emission, especially when estimating the spin with the continuum-fitting method which assumes the disc terminates at the innermost stable circular orbit at all times.
Predicting convective blueshift and radial-velocity dispersion due to granulation for FGK stars
Authors: Dalal S , Haywood R D , Mortier A , Chaplin W J , Meunier N
Published: August 2023

To detect Earth-mass planets using the Doppler method, a major obstacle is to differentiate the planetary signal from intrinsic stellar variability (e.g. pulsations, granulation, spots, and plages). Convective blueshift, which results from small-scale convection at the surface of Sun-like stars, is relevant for Earth-twin detections as it exhibits Doppler noise of the order of 1 $\rm m\, s^{-1}$. Here, we present a simple model for convective blueshift based on fundamental equations of stellar structure. Our model successfully matches observations of convective blueshift for FGK stars. Based on our model, we also compute the intrinsic noise floor for stellar granulation in the radial-velocity observations. We find that for a given mass range, stars with higher metallicities display lower radial-velocity dispersion due to granulation, in agreement with magnetohydrodynamic simulations. We also provide a set of formulae to predict the amplitude of radial-velocity dispersion due to granulation as a function of stellar parameters. Our work is vital in identifying the most amenable stellar targets for Extreme Precision Radial Velocity surveys and radial velocity follow-up programmes for TESS, CHEOPS, and the upcoming PLATO mission.
Centromere Plasticity With Evolutionary Conservation and Divergence Uncovered by Wheat 10+ Genomes
Authors: Ma Huan , Ding Wentao , Chen Yiqian , Zhou Jingwei , Chen Wei , Lan Caixia , Mao Hailiang , Li Qiang , Yan Wenhao , Su Handong
Published: August 2023

Centromeres (CEN) are the chromosomal regions that play a crucial role in maintaining genomic stability. The underlying highly repetitive DNA sequences can evolve quickly in most eukaryotes, and promote karyotype evolution. Despite their variability, it is not fully understood how these widely variable sequences ensure the homeostasis of centromere function. In this study, we investigated the genetics and epigenetics of CEN in a population of wheat lines from global breeding programs. We captured a high degree of sequences, positioning, and epigenetic variations in the large and complex wheat CEN. We found that most CENH3-associated repeats are Cereba element of retrotransposons and exhibit phylogenetic homogenization across different wheat lines, but the less-associated repeat sequences diverge on their own way in each wheat line, implying specific mechanisms for selecting certain repeat types as functional core CEN. Furthermore, we observed that CENH3 nucleosome structures display looser wrapping of DNA termini on complex centromeric repeats, including the repositioned CEN. We also found that strict CENH3 nucleosome positioning and intrinsic DNA features play a role in determining centromere identity among different lines. Specific non-B form DNAs were substantially associated with CENH3 nucleosomes for the repositioned centromeres. These findings suggest that multiple mechanisms were involved in the adaptation of CENH3 nucleosomes that can stabilize CEN. Ultimately, we proposed a remarkable epigenetic plasticity of centromere chromatin within the diverse genomic context, and the high robustness is crucial for maintaining centromere function and genome stability in wheat 10+ lines as a result of past breeding selections.
Angioleiomyoma mimicking a swollen bursa on first metatarsophalangeal joint accompanying with hallux valgus deformity
Authors: Matsuda Kotaro , Hirao Makoto , Noguchi Takaaki , Okamura Gensuke , Hoshida Yoshihiko , Etani Yuki , Ebina Kosuke , Okada Seiji , Hiraoka Koji , Hashimoto Jun
Published: August 2023

We present a case of a patient who underwent a modified scarf osteotomy and tumour excision based on a preoperative diagnosis of hallux valgus deformity and accompanying bursitis. Subsequent histopathological examination revealed that the tumour was an angioleiomyoma. While tumours around the first metatarsophalangeal (MTP) joint are typically associated with gouty nodules, infections, or swollen bursa (bursitis) in patients with hallux valgus deformity, the occurrence of soft tissue tumours in this area is rare. Moreover, angioleiomyoma is an even rarer form of soft tissue tumour and is seldom suspected prior to resection. To our knowledge, there have been no reports of angioleiomyoma arising in the first MTP joint. However, it is important to consider the possibility of an atypical tumour in cases where soft tissue masses are present, even in patients with hallux valgus deformity, and to perform at least imaging tests such as ultrasound and magnetic resonance imaging before surgery. This prospect should always be kept in mind.
BSBM-06 UNRAVELING THE IMMUNE MICROENVIRONMENT OF BRAIN METASTASIS FROM LUNG ADENOCARCINOMA
Authors: Souza Vanessa G P , de Araújo Rachel P , Santesso Mariana R , Seneda Ana Laura , Minutentag Iael W , Hamamoto Filho Pedro T , Marchi Fábio A , Drigo Sandra A , Lam Wan L , Reis Patricia P
Published: August 2023

Brain metastasis (BM) is a common complication of advanced lung adenocarcinoma (LUAD) and is associated with significantly poor prognosis and reduced quality of life. The immune system plays a critical role in the development and progression of BM, as well as in response to therapy. Herein, we used Next-Generation Sequencing (NGS) and array technologies to elucidate the immune landscape of LUAD-BM. NGS data from BM and primary tumors (T): RNA-Seq (n=24; 13 BM and 11 T), microarray (n=140; 63 BM and 77 T) were used for quantifying the immune cell fractions by CIBERSORT. Additionally, single-cell (scRNA-seq) data (n=57,774 cells; 23 BM samples) were used for data validation. Results showed that resting memory T CD4 comprised the largest cellular fraction (17.4%) of the total immune cells in BM. Furthermore, the fraction of resting dendritic cells (DC) was lower in BM vs. T, while the neutrophil fraction was higher (p<0.05). ScRNA-seq confirmed the presence of DC and neutrophils in BM, identifying multiple subsets of DC (cDC1, cDC2/MoDC, and DC3) that are highly conserved across solid human cancers with cDC2/MoDC as the most frequent subpopulation among dendritic cells. Therefore, our results show a different immune profile between BM and primary LUAD. The immune environment of LUAD-BM is highly suppressed, accompanied by enriched T cell subpopulations predicted as immature T cells. The identification of cDC2/MoDC subpopulations in LUAD-BM replicates the findings observed in BM from melanoma patients. It has been shown that cDC2 can interact with CD4+ T cells to promote anti-tumor immune responses. Our findings elucidate the profiles of LUAD-BM immune microenvironment, comprehensively identifying specific immune subpopulations with important roles in the establishment and progression of BM from LUAD.
BSBM-12 STAT3 EXPRESSION IN BRAIN METASTASES FROM BREAST CANCER: CORRELATIONS WITH DIFFERENT MOLECULAR SUBTYPES AND CLINICAL OUTCOME
Authors: Pellerino Alessia , Bruno Francesco , Bertero Luca , Bellini Elisa , Beano Alessandra , Montemurro Filippo , Valiente Manuel , Rudà Roberta , Soffietti Riccardo
Published: August 2023

BACKGROUND

STAT3 expression in peritumoral reactive astrocytes (RA) of brain metastases (BM) from breast cancer (BC) may favor a pro-metastatic environment.

MATERIAL AND METHODS

105 BM specimens from BC were identified from the biobank of Pathology Unit of University of Turin and Spanish national BrM network (RENACER). pSTAT3 expression was scored in RA of peritumoral tissue according to Priego et al. (Nat Med 2018). Clinical, molecular data, and intracranial progression (i-PFS) were retrospectively retrieved.

RESULTS

Median age was of 50 years (range 46–54). 31/105 patients (29.5%) had luminal BM, 35/105 (33.3%) had HER2-positive BM, and 39/105 (37.1%) had triple negative BM. Immunohistochemistry for GFAP and pSTAT3 was feasible in 88/105 (83.8%). 49/88 (55.7%) showed positive staining of pSTAT3, of which 15/88 (17%) scored with 3, 34/88 (38.6%) with 2, 28/88 (31.9%%) with 1, and 11/88 (12.6%) with 0 (negative). High pSTAT3 expression (score 2-3) was observed in 27/34 (79.4%) triple negative BM, and in 18/30 (60.0%) HER2-positive BM, while most of luminal BM (20/24 – 83.3%) had low or absent pSTAT3 expression. Median i-PFS was 16.0 months (range 7-80): low pSTAT3 BM (score 0-1) had a median i-PFS of 11 months versus 8 months for high pSTAT3 BM (score 2-3) (HR 0.4; p=0.0123). A shorter median i-PFS was observed in high pSTAT3 triple negative BM (4 months) as compared with low pSTAT3 BM (20 months). Conversely, i-PFS of high pSTAT3 BM (7 months) was similar to low pSTAT3 BM (7 months) in HER2-positive BC.

CONCLUSION

pSTAT3 expression in RA of triple negative BM and HER-2 positive BM is higher than in luminal BM. Of note, patients with high pSTAT3 triple negative BM progressed earlier in comparison with those with low pSTAT3, suggesting that pSTAT3 expression has an influence on the outcome.
BSBM-13 MELANOMA CELLS PRODUCE A SUSPENSION SUB-POPULATION THAT DRASTICALLY DISRUPTS THE BLOOD-BRAIN BARRIER ENDOTHELIUM
Authors: Anchan Akshata , Spurling Dayna , Hucklesby James , Finlay Graeme , Angel Kate , Graham E Scott
Published: August 2023

Melanoma metastasizes to the brain with high propensity. Brain metastasis requires cancer cells to breach the blood-brain barrier (BBB) endothelium, which forms the first line of defence against blood-borne pathogens. An increasing number of molecules are discussed in BBB disruption, and their importance varies across melanoma and endothelial cell lines. This diversity in literature proposes that cancer cells of the same cancer type employ different modes of metastasis. This study shows an example of the difference in migration capabilities of adherent melanoma cells and a suspension sub-population. We used Electric Cell-substrate Impedance Sensing (ECIS) to assess changes in human brain endothelial barrier function upon adding human melanoma lines. Several melanoma lines induced brain endothelial barrier disruption within the first few hours of addition. Intriguingly, the suspension population of melanoma cells disrupted the endothelial barrier faster and more drastically than the adherent counterpart. Time-lapse imaging revealed that the suspension population used a transcellular route of invasion compared to the paracellular route used by the adherent cells. Confocal microscopy supported this, showing clear differences in the physical interaction of the suspension subtype with the brain endothelium, compared to the adherent cells. Flow cytometry and NanoString technology allowed characterization of the melanoma lines, showing that the suspension subtype protein composition differs from their adherent counterpart. We hypothesize that melanoma cells may produce specific subtypes that are more invasive, which can accelerate migration through the brain endothelium. We stress the importance of investigating the composition of melanoma cells and their bi-products when researching cancer metastasis. Once successfully within the brain parenchyma, these cancer cells are effectively separated from the peripheral adaptive immune system, designed to detect and eliminate them. Therefore, preventing cancer cell migration into the brain is an attractive consideration, as they are considerably more targetable whilst still in the blood.
BSBM-22 CHARACTERIZATION OF CIRCULATORY SHEAR STRESS-INDUCED MOLECULAR CHANGES IN LUNG ADENOCARCINOMA CELLS AND IMPLICATIONS IN BRAIN METASTASIS
Authors: Marenco-Hillembrand Lina , McKevitt Chase , Bamimore Michael , Wickland Daniel , Schiapparelli Paula , Maharjan Sushila , Zhang Yu Shrike , Quinones-Hinojosa Alfredo , Chaichana Kaisorn L
Published: August 2023

INTRODUCTION

Lung cancer is the most common tumor to metastasize to the brain, as 40% of patients develop brain metastasis (BM). Once diagnosed, survival is only 6.5-10 months. A potential target to prevent BM is circulating tumor cells (CTCs). The mechanisms that mediate a CTCs adaptation to the harsh environment of circulation and BM have not been elucidated. We have demonstrated that primary lung cancer cells (LCCs) subjected to circulation have increased migration across brain endothelial cell monolayers, increased side population, and decrease survival in rodents when injected intracardially vs plated controls.

METHODS

We engineered a microfluidic device capable of subjecting tumor cells to prolonged circulatory shear stress (CSS) that allows the isolation/modeling of CTC-like cells. Primary LCCs (A549, H1563) were subjected to circulation, suspension, or plated (2D) for 72h as controls. At this time point, LCCs were collected, and total mRNA was extracted. Samples were submitted for RNA sequencing. Weighted gene co-expression network analysis (WCGNA) and Ingenuity Pathway Analysis were performed. (FC >2 and p-value <0.05).

RESULTS

Transcriptomic analysis indicates that cells subjected to CSS activate specific gene networks involved in cell survival, migration, invasion, adhesion of tumor cells, and cytoskeletal reorganization (z-score: >2, p-value: 0.05). Canonical pathways in CTCs included ILK-signaling and Xenobiotic Metabolism. LCCs exposed to CSS had increased expression of multidrug resistance pumps ABCC2, ABCF2 (P:<0.001), and side population on flow cytometry (P: <0.05). The top differentially expressed genes in CTC-like cells (MMP1, ANGPTL4, and CEMIP) were involved in the invasion, angiogenesis, and pre-metastatic niche (PMN) formation of BM.

CONCLUSION

LCCs that survive CSS have increased expression of genes associated with migration, invasion, and chemoresistance compared to 2D controls. Targeting genes in CTCs that mediate survival and preparation of the PMN may be useful in preventing BM.
LMAP-03 OUTCOME OF BRAIN METASTASES TREATED WITH GAMMA KNIFE STEREOTACTIC RADIOSURGERY (GKSR): COHORT RETROSPECTIVE STUDY ON 205 CASES
Authors: Bankole Nourou Dine Adeniran , Melhaoui Adyl , Arkha Yasser , Semmar Afaf , Bouyakhlef Khalid , Boutarbouch Mahjouba , Jiddane Mohamed , El Khamlichi Abdeslam
Published: August 2023

BACKGROUND

Brain metastases (BMs) are the most common expansive intracranial lesions in adults. Approximately 50% of patients diagnosed with new brain metastases have more than one brain metastasis at the time of diagnosis.

OBJECTIVE

We report our experience of brain metastases treated with GKSR and evaluate the outcome.

METHODS

Patients treated by Gamma Knife stereotactic radiosurgery (GKSR) in our institution between 2008 and 2021 for BM were recorded retrospectively.

RESULTS

A total of 205 patients (56.6% females) were included, with a median age of 59 (25-83) years old. Breast (n=85, 42.5%) and lung (n=76, 38%) were the common original locations for the primary tumors (Table 1). There were 103 patients (50.3%) with single BM and 102 patients (49.7%) with multiple BM⩾2. The median number of multiple BM treated was 4 (2-43). The overall mean survival time was 6.00(95% CI, 5.07-6.93) months for all BM. The median percentage of tumor control after radiosurgery treatment was 65% (20-99) over the median follow-up time of 6.00(3-84) months. In the overall population, the 1-year OS rate was 37.55%, the 2-year OS rate was 25.12%, and the 5-year OS was 18.51%. The mean survival time among patients with BM was higher in those with multiple BM than those with single BM ([10 (95%CI 6.67-13.33) months vs 5(4.21-5.70) months, P (0.03)]). Retreatment, tumor stability (control), and progression influence the overall survival of BM, whether single or multiple (P<0.001).

CONCLUSION

Stereotaxic Radiosurgery provides good results in terms of Overall survival and better Quality of Life for BM, whether single or multiple. Stability and retreatment influenced the overall survival of BM.
LMAP-04 CHOOSING WISELY BETWEEN RADIOTHERAPY DOSE-FRACTIONATION SCHEDULES: THE MOLECULAR GRADED PROGNOSTIC ASSESSMENT (MOLGPA) FOR ELDERLY GLIOBLASTOMA (EGBM-MOLGPA)
Authors: Lee Hye In , Kim Jina , Kim In Ah , Lee Joo Ho , Cho Jaeho , Yoon Hong In , Wee Chan Woo
Published: August 2023

This study aimed develop a prognostic model integrating genomic characteristics in patients with elderly glioblastoma (eGBM), and compare the efficacy between conventionally fractionated radiotherapy (CFRT) vs. hypofractionated radiotherapy (HFRT). Patients aged ≥65 years who underwent radiotherapy for IDH-wildtype eGBM between 2006 and 2021 were included. Patients planned for a ≥6-week or ≤4-week radiotherapy were regarded as being treated with CFRT (334 patients; median, 60 Gy in 30 fractions) or HFRT (239 patients; median, 45 Gy in 15 fractions), respectively. We developed the molecular graded prognostic assessment score for eGBM (eGBM-molGPA) and assigned 0.0, 0.5, and 1.0 points in proportion to the corresponding hazard ratio (HR) of each prognostic factor for overall survival (OS). Temozolomide-based chemoradiation was applied for 86% of patients. With a median follow-up of 17.4 months, the median OS was 18.7 months for CFRT plus temozolomide group, 15.1 months for HFRT plus temozolomide group, and 10.4 months for RT alone group. The eGBM-molGPAwas established based on prognostic factors from multivariate analysis (performance, extent of resection, temozolomide, methylation of the MGMT promoter, subventricular zone involvement, temporalis muscle thickness, and the mutation status of TERT promoter and TP53 gene) and patients were allocated to three risk groups (high risk, total score 3.0–4.5; intermediate risk, 1.5–2.5; low risk, 0.0–1.0). Patients treated with CFRT plus temozolomide had significantly improved OS compared to those treated with HFRT plus temozolomide or radiotherapy alone in the low and intermediate risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options. CFRT plus temozolomide can be a more effective strategy for selected eGBM patients compared to HFRT. For high-risk patients, a protracted treatment schedule might not be beneficial. The novel eGBM-molGPA can be used as a clinical tool for choosing wisely among radiotherapy options.
LMAP-09 RECAPITULATING LASER INTERSTITIAL THERMAL THERAPY IN PRECLINICAL BRAIN TUMOR MODELS
Authors: Haskell-Mendoza Aden , Wachsmuth Lucas , Fecci Peter
Published: August 2023

Laser interstitial thermal therapy (LITT) is a minimally-invasive option for cytoreduction of recurrent or otherwise difficult-to-access intracranial tumors. Relative to resection, ablated tumor tissue remains in situ, facilitating recognition of tumor antigens and a targetable immune response. To investigate the immune consequences of LITT, we developed a model of stereotactic laser ablation for use with existing syngeneic glioma and intracranial metastasis cell lines. A 1064 nm diode-based Nd:YAG laser (Monteris Medical) was used to thermally ablate normal brain tissue or CT-2A tumors in C57BL6/J mice. Ablations were performed at 10 days post-implantation at + 2 ML, + 1 AP, -3 DV using a stereotactic frame. Simultaneous temperature measurements were taken using a thermocouple probe implanted to the same depth 2 mm posterior. We first used serial T2-weighted MRI imaging to accurately track the tumor growth characteristics and identify a safe lesion size for ablation, selecting 10 days post-implantation for subsequent experiments and 2 mm posterior as the ideal position to monitor temperature at the lesion edge. To assess the thermal characteristics of our laser, we ablated mouse brains at 1 W and 2 W for 30, 60, or 90 seconds each, finding that 1 W for 90 seconds produced an ablation that did not char or coagulate tissue outside the ablation zone and recapitulated human ablation findings on H&E staining 24h post-LITT. We next implanted CT-2A tumors for ablation with the selected dose, following mice for survival between the LITT and sham-ablated groups. A subset of mice were imaged using T2-MRI at 1, 3, 7, and 14 days post-surgery. Our model recapitulates the essential clinicopathological findings of LITT and is well suited apply to a variety of intracranial tumor models and LITT-adjunctive therapies.
LMAP-11 CYSTIC BRAIN METASTASES OUTCOMES FOLLOWING GAMMA KNIFE RADIOTHERAPY
Authors: Amidon Ryan , Livingston Katie , Kleefisch Christopher , Straza Michael , Puckett Lindsay , Schultz Christopher , Mueller Wade , Connelly Jennifer , Noid George , Morris Kirk , Bovi Joseph
Published: August 2023

BACKGROUND

The response of cystic brain metastases (BMets) to radiotherapy is poorly understood, with conflicting results regarding local control (LC), overall survival (OS), and treatment-related toxicity. This study aims to examine the role of Gamma Knife (GK) in managing cystic BMets.

METHODS

Volumetric analysis was conducted to measure tumor and edema volume at the time of GK and follow-up MRI studies. We evaluated the association of 4 variables with survival using Cox regression analysis and used the Kaplan-Meier method to estimate median survival times (MST).

RESULTS

Between 2016 and 2021, 54 patients with 83 cystic BMets were treated with GK at our institution. Lung cancer was the most common pathology (51.9%), followed by breast (13.0%). The mean target volume was 2.7 cc (range, 0.1-39.0 cc) and the mean edema volume was 13.9 cc (range, 0-165.5 cc). The median prescription dose of single fraction and fractionated GK was 20 Gy (range, 14-27.5 Gy). With a median follow-up of 8.9 months, MST was 11.1 months, OS was 33.3%, and the one-year LC rate was 75.9%. GK was associated with decreased tumor and edema volumes over time, although 68.5% of patients required steroids post-GK. Patients whose tumors grew beyond baseline following GK received significantly more pre-GK whole-brain radiation therapy (WBRT) than those whose tumors declined following GK. Higher age at diagnosis of BMets and pre-GK systemic therapy were associated with worse survival, with an MST of 7.8 months in patients who received it compared to 23.3 months in those who did not.

CONCLUSIONS

Pre-GK WBRT may select for BMets with increased radioresistance. This study highlights the ability of GK to control cystic BMets with the cost of high post-treatment steroid use.
LMAP-12 TUMOR TREATING FIELDS (TTFIELDS) REAL-WORLD EXPERIENCE IN NEWLY DIAGNOSED GLIOBLASTOMA: A SYSTEMATIC LITERATURE REVIEW AND META-ANALYSIS OF OVERALL SURVIVAL
Authors: Ballo Matthew T , Conlon Patrick , Lavy-Shahaf Gitit , Kinzel Adrian , Vymazal Josef , Rulseh Aaron M
Published: August 2023

BACKGROUND

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability and tumor progression by a multi-modal mechanism of action. TTFields therapy is FDA-approved for newly diagnosed glioblastoma (ndGBM) based on results from the randomized, phase 3 EF-14 study (NCT00916409). We assessed the overall survival (OS) benefit of adding TTFields therapy to standard of care (SOC) in ndGBM, as well as the relationship between OS and time using the device.

METHODS

A systematic literature review (PubMed, Embase, and Cochrane Library) identified single-cohort and comparative clinical studies that assessed survival in patients with ndGBM who received TTFields therapy. Inter-study heterogeneity was quantified using the Higgins I2 statistic and Cochran Q test. A distribution-free random-effects method was used to pool survival curves.

RESULTS

Nine studies were identified that evaluated survival with TTFields therapy in ndGBM. Of these, 7 studies (1430 patients) that compared TTFields therapy with SOC to SOC alone, were included in the pooled analysis for OS. The pooled data showed significantly longer OS with TTFields therapy/SOC versus SOC alone (HR: 0.63; 95% CI, 0.53-0.75; P<0.001). A sensitivity analysis indicated that the effect was robust and independent of any individual study. In post-approval studies, pooled median OS was 22.2 months (95% CI, 17.3-42.6) for TTFields therapy/SOC and 17.3 months (95% CI, 13.6-22.0) for SOC alone. Gross total resection was generally more prevalent in the real-world setting, irrespective of TTFields therapy use. Average recommended device usage of ≥75% was associated with prolonged OS vs <75% usage in 6 studies (pooled HR: 0.60; 95% CI, 0.48-0.73; P<0.001).

CONCLUSIONS

Pooled analysis of comparative TTFields therapy studies suggests a significant survival benefit with TTFields added to SOC for patients with ndGBM, and that a recommended 75% usage rate may be clinically meaningful in the real-world setting.
LMAP-18 ADAPTING LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR TREATMENT OF INTRACRANIAL LESIONS IN CANINES
Authors: Mariani Chris , Wachsmuth Lucas , Ruterbories Laura , Tsvankin Vadim , Bramall Alexa , Tyc Richard , Fecci Peter
Published: August 2023

Malignant gliomas are devastating intracranial tumors with dismal prognoses that impose unique therapeutic challenges. Treatment options include surgical resection, radiation, and chemotherapy, but efficacy is limited and carries associated morbidity. Promise persists for newer modalities, such as immune-based platforms, but the blood-brain barrier (BBB) restricts intracranial therapeutic access, limiting success. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of brain tumors and other intracranial lesions. During LITT, a laser probe is stereotactically introduced through a small skull burr hole into the lesion. Continuous MRI is used to conduct real-time temperature monitoring via software-based calculation of cumulative thermal dosage zones. LITT is not only capable of ablating neoplastic tissue, but can also open the BBB in peritumoral regions, and thus may synergize with other emerging therapies. We adapted a commercially available LITT system (Monteris Medical) for use in dogs with intracranial lesions. Canine cadavers were used to optimize LITT procedures before employing this platform in live dogs. Our approach consists of 1. obtaining volumetric, T1-weighted, MRI studies to plan trajectories to intracranial targets, 2. fixing canine patients to a surgical bed and registering them for surface matching to a volume rendered image, 3. using an integrated instrument holder (Varioguide, Brainlab) to guide drilling of 4.5 mm skull burr holes for placement of self-tapping titanium “mini-bolts” (Monteris Medical), and 4. introducing the laser catheter probe through the mini-bolts for lesion ablation in the MRI suite. This method allows for rigid stereotaxy, successful neuronavigation, and a minimally invasive approach. We have successfully performed LITT on four canine patients with spontaneously occurring intracranial gliomas and plan to treat additional canine patients with intracranial lesions. Future studies will explore combination therapeutic platforms, including immunotherapy and gold nanoparticles to improve the efficiency and specificity of tumor ablation.
NEIM-13 THE PROGNOSTIC ROLE OF VENTRICULAR SIZE AND ITS DYNAMICS IN PATIENTS WITH LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS
Authors: Le Rhun Emilie , Devos Patrick , Seystahl Katharina , Jongen Joost , Gramatzki Dorothee , Roth Patrick , van den Bent Martin , Brandsma Dieta , Weller Michael
Published: August 2023

BACKGROUND

Hydrocephalus is a common radiological sign in patients with leptomeningeal metastasis (LM) from solid tumors and can be assessed using the Evans index (EI) with high interrater agreement. Here we explored the prognostic value of ventricular size at diagnosis and during the disease course of LM.

METHODS

We assembled a cohort of 113 adult patients with a diagnosis of LM from solid extra-CNS tumors and explored the association of ventricular size assessed by the EI at diagnosis, of its modification between diagnosis and evaluation at first follow-up and at first progression, with outcome.

RESULTS

Median age was 58.2 years (interquartile range (IQR) 46.1-65.7), 41 patients (36%) were male, the most frequent cancers were lung cancer (n=39, 35%), breast cancer (n=36, 32%) andmelanoma (n=23, 20%). The median EI at baseline was 0.28 (IQR 0.26-0.31), the EI value was 0.27 or more in 67 patients (59%) and 0.30 or more in 37 patients (33%). At LM progression, an increase of EI of 0.01 or more was noted in 18 of 34 patients (53%). The median overall survival was 2.9 months (IQR 1-7.2). Patients with a baseline EI of 0.26 or less had a longer survival than those with an EI of 0.27 or more (5.3 months, IQR 2.4-10.8, versus 1.3 months, IQR 0.6-4.1) (p=0.006). Among patients with follow-up scans available, median overall survival was 9.7 months (IQR 5.6-21.4) for patients with stable or decreased EI at first follow-up as opposed to 6.4 months (IQR 3.2-10.5) for those with an increase in the EI (p=0.292).

CONCLUSION

The EI at baseline is prognostic in LM. An increase of EI during the follow-up is associated with inferior LM-PFS. An independent validation cohort with larger sample size and evaluation of confounding factors will help to better define the role of EI assessments in LM.
SDPS-06 A 4 YEAR-OLD GIRL WITH EMBRYONAL RHABDOMYOSARCOMA IN RETROAURICULAR AND MIDDLE EAR : A RARE CASE REPORT FROM INDONESIA
Authors: Anugrah Diko , Rahmartani Ludy Dhyani
Published: August 2023

Rhabdomyosarcoma is the most common sarcoma of childhood, and this tumor is the third most common neoplasm after neuroblastoma and nephroblastoma. Rhabdomyosarcomas may originate in any anatomical site, occurring predominantly in head and neck regions, orbits, skull base, nasal cavity, and nasopharynx, where there is little or no musculoskeletal tissue. The involvement of the ear and mastoid bone in rhabdomyosarcoma is uncommon. The embryonal rhabdomyosarcoma includes about 60– 70% of rhabdomyosarcoma cases. A four years-old girl presented with pain in neck and difficult to moving, there was a mass in the left auricular that was getting bigger. 4 days prior to admission, there was a drooping mouth to the left, the voice sounds hoarse, but there was no weakness in the side and no loss of consciousness. On physical examination, there was a N.VII palsy, without hyperreflexia, paraplegia, and nystagmus. High resolution Mastoid CT-Scan showed a characteristic malignant solid mass involving the external acoustic canal and the left tympanic and mastoid cavities, destroying the auditory and temporal bones, involving the left internal acoustic canal, and reaching the left nasopharynx, extending into the intracranial region of the left cerebellopontine angle and left temporal duramater. In Pathology examination showed Tumor cells are spherical, spindle-shaped with pleomorphic nuclei, hyperchromatic, coarse chromatin, vesicular, some with real nuclear daughters, eosinophilic cytoplasm. Mitosis is discovered. eccentricallynucleated cells with eosinophilic cytoplasm, suggesting rhabdomyoblast differentiation, some with a "tadpole" appearance, and conclusion according to embryonal rhabdomyosarcoma. The patient is treated with chemotherapy using Vincristine, Actinomycin-D, and Ifosfamide.
SDPS-08 OSSEOUS METASTASES IN H3G34-MUTANT DIFFUSE HEMISPHERIC GLIOMAS
Authors: Yu Nina , Lee Han Sung , Raslan Osama , Jin Lee-Way , Aboud Orwa
Published: August 2023

Subset of patients with H3G34 gliomas may present with extra-CNS metastasis further complicating both diagnosis and treatment. We describe a case of a 19-year-old female presenting initially with focal motor seizure in right leg along with leg pain. MRI of the leg showed an ill-defined right distal femur expansile osteolytic lesion with central fluid signal, thick rim enhancement, endosteal scalloping, cortical invasion, and smooth enhancing periosteal reaction/soft tissue extension associated with surrounding enhancing marrow signal abnormality worrisome for lesion extension. Contrast brain MRI exhibited multiple frontal and partial lobe T2 FLAIR hyperintense lesions. The largest lesion demonstrated contrast enhancement, internal foci of restricted diffusion, and a focus of intratumoral hemorrhage. A whole-body PET/CT showed intensely FDG-avid lytic lesion in the right distal femur, with FDG activity along the biopsy tract. Hypermetabolic lytic metastases to the right femoral head and mid-sacral body were also observed. A craniotomy with brain lesion biopsy two months later indicated preliminary histopathology of malignant small round blue cell neoplasm. A biopsy from the distal right femur was non-diagnostic of malignancy but a sacral bone biopsy reported malignant small blue cell neoplasm, consistent with involvement by the patient's known cranial neoplasm. Final pathological diagnosis including molecular diagnostics was consistent with WHO grade 4 IDH-wildtype H3G34 mutant diffuse hemispheric glioma with osseous metastases. Patient was treated with chemoradiotherapy with temozolomide (TMZ). Following the sixth cycle of TMZ, MRI brain imaging was stable. Apart from holocephalic headaches, the patient had no significant medication side effects and was seizure-free. A second whole-body PET scan showed improvement and interval decrease in FDG uptake of the sacrum and right femoral head. Given the stress that patients with H3G34 can experience and the poor prognosis, it is imperative to expand our knowledge and ascertain accurate screening and diagnostic methodologies.
SDPS-16 CYTOLOGIC AND SEROLOGIC RESPONSE WITH INTRATHECAL METHOTREXATE IN A PATIENT WITH LEPTOMENINGEAL CARCINOMATOSIS FROM OVARIAN CANCER
Authors: Cordova Christine , Abdallah Kawther , Daniela Chiciuc , Tsay Jawad
Published: August 2023

Leptomeningeal Carcinomatosis (LMC) is a rare complication of ovarian cancer and there is no established first-line therapy. Treatment of LMC in general can include intrathecal chemotherapy and radiation as well as relevant systemic therapies with CNS activity. We employed the commercially available Biocept CNSide™ assay to detect, quantify, and molecularly characterize tumor cells in the cerebrospinal fluid (CSF). We report a 66-year-old female who was initially diagnosed with stage 3C serous ovarian carcinoma who developed brain metastases one year later, managed with resection and stereotactic radiosurgery. Serum CA-125 continued to rise despite local therapy and subsequent MRI demonstrated leptomeningeal enhancement of bilateral internal auditory canals and the cauda equine concerning for LMC. Exam was notable for a left cranial nerve VII palsy and gait instability. Lumbar puncture with CNSide quantified a baseline tumor cell count and identified HER2 amplification on tumor cells. She began intrathecal methotrexate (IT MTX), followed by decline in both CSF tumor cell count and serum CA-125. She demonstrated clinical benefit with improved imbalance. Over time, she experienced nausea and vomiting with IT MTX and was switched to anti-HER2 therapy with off-label lapatinib and she enjoyed improved quality of life. Notably, tumor cells lost HER2 amplification, raising possibility of clone selection. She later experienced focal progression of LMC and before other therapy could be offered, she succumbed to illness approximately one year from the initial radiographic finding of leptomeningeal enhancement, exceeding the average survival for LMC.Here we demonstrate the activity of IT MTX in ovarian LMC as well as the utility of serial CSF tumor quantification for disease monitoring in conjunction with imaging and the physical exam. Further studies are warranted to evaluate LMC therapy in a prospective setting as well as the possibility of clone selection in the CNS with targeted therapy.
SDPS-29 SERUM-DERIVED CD47 AS A MARKER OF TUMOR BURDENAND OUTCOME IN GBM PATIENTS – CORRELATIVE ANALYSISOF TUMOR LOCATION, RADIATION THERAPY VOLUMES,AND SURVIVAL
Authors: Jagasia Sarisha , Krauze Andra , Zhao Yingdong , Li Ming-Chung , Tasci Erdal , Zgela Theresa Cooley , Sproull Mary , Mackey Megan , Tofilon Philip , Camphausen Kevin
Published: August 2023

Glioblastomas (GBM) are the most aggressive central nervous system tumors exhibiting near universal recurrence following resection and chemoradiation (CRT). CD47 is an integrin-associated transmembrane protein associated with immunomodulation, invasion, and stemness that is highly expressed in GBM. We tested the hypothesis patient serum-derived CD47 measured pre vs. post-CRT may be related to tumor burden by exploring its association with tumor dissemination in the brain, RT volumes, and outcomes. CD47 was analyzed using an aptamer-based SOMAscan proteomic assay on serum collected pre and post CRT for 82 individuals with a pathologic diagnosis of GBM. Clinical features (tumor location (cortical/periventricular), gross tumor volumes (GTVT1, GTVT2), and outcome (overall survival (OS), progression-free survival (PFS)) were analyzed in conjunction with alteration in CD47 levels. Alteration in CD47 level was associated with OS (HR = 32.34 CI: 3.520 - 288.3, p = 0.0004053) and PFS (HR =8.5, p = .0008 CI: 0.2291-4.011). Expression of CD47 increased after CRT (p = .022). Patients with periventricular tumors had higher expression of CD47 pre vs. post CRT (p = 0.0188) and worse OS (median 13 vs. 25 months) and PFS (median 5 vs. 10 months) as compared to patients with strictly cortical tumor presence. A positive correlation was identified between GTVT1 and GTVT2 and CD47 expression levels (p = .0006). Lower CD47 expression values were associated with higher survival probability (p = .013). The stratification of CD47 expression levels yielded increasingly significant results with the separation of discrete survival groups (p = .00013), indicating clinically distinct subtypes of GBM. Tumor location (cortical vs. periventricular) and GTVT1 correlated with OS and PFS (p<0.05), unlike GTVT2 in this cohort in the absence of CD47 expression level. CD47 expression levels correlate with tumor location, RT volumes, OS, and PFS with distinct GBM subtypes potentially stratified via serum CD47 expression levels.
SDPS-35 TUMOR-RELATED EPILEPSY IN HIGH-GRADE GLIOMA: A LARGE SERIES SURVIVAL ANALYSIS
Authors: Rilinger Ryan , Guo Lydia , Sharma Akshay , Grabowski Matthew , Lobbous Mina
Published: August 2023

BACKGROUND

Seizures are a common clinical occurrence throughout the disease course in glioblastoma (GBM). While many studies have explored the impact of surgical and medical treatment for GBM on seizure incidence and prevalence, limited study has been directed towards the prognostic effect of seizures occurring in the post-treatment setting.

METHODS

We retrospectively reviewed 238 patients with histologically-confirmed high grade glioma treated at our institution between 2018 and 2021. Seizure presentation was classified as early onset (occurring at the time of GBM presentation), or late onset (first seizure occurring after beginning standard surgical and medical treatment). Using a multivariate Cox proportional-hazards model, hazard ratios were assessed for timing of seizure presentation, as well as other clinical and tumor-associated variables.

RESULTS

Incidence of first seizure after the onset of treatment was found to be associated with improved overall survival (HR=0.66, p=0.03), while increasing age (HR 1.02, p=0.007) and deep/midline tumor location (HR 1.86, p=0.003) were associated with decreased overall survival.

CONCLUSION

While seizure at presentation may be associated with better survival in high-grade glioma, more analysis is underway to confirm the finding in a larger cohort and to evaluate the impact of molecular alterations in seizure incidence and management. Further study in this patient cohort utilizing detailed next-generation sequencing will evaluate the association of the patient-specific tumor profile on seizures and overall survival.