bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of heterogeneous stress in earthquake cycle models of the Hikurangi–Kermadec subduction zone
Authors: Liao Yi-Wun Mika , Fry Bill , Howell Andrew , Williams Charles A , Nicol Andrew , Rollins Chris
Published: August 2024

Seismic and tsunami hazard modelling and preparedness are challenged by uncertainties in the earthquake source process. Important parameters such as the recurrence interval of earthquakes of a given magnitude at a particular location, the probability of multifault rupture, earthquake clustering, rupture directivity and slip distribution are often poorly constrained. Physics-based earthquake simulators, such as RSQSim, offer a means of probing uncertainties in these parameters by generating long-term catalogues of earthquake ruptures on a system of known faults. The fault initial stress state in these simulations is typically prescribed as a single uniform value, which can promote characteristic earthquake behaviours and reduce variability in modelled events. Here, we test the role of spatial heterogeneity in the distribution of the initial stresses and frictional properties on earthquake cycle simulations. We focus on the Hikurangi–Kermadec subduction zone, which may produce Mw > 9.0 earthquakes and likely poses a major hazard and risk to Aotearoa New Zealand. We explore RSQSim simulations of Hikurangi-Kermadec subduction earthquake cycles in which we vary the rate and state coefficients (a and b). The results are compared with the magnitude-frequency distribution (MFD) of the instrumental earthquake catalogue and with empirical slip scaling laws from global earthquakes. Our results suggest stress heterogeneity produces more realistic and less characteristic synthetic catalogues, making them particularly well suited for hazard and risk assessment. We further find that the initial stress effects are dominated by the initial effective normal stresses, since the normal stresses evolve more slowly than the shear stresses. A heterogeneous stress model with a constant pore-fluid pressure ratio and a constant state coefficient (b) of 0.003 produces the best fit to MFDs and empirical scaling laws, while the model with variable frictional properties produces the best fit to earthquake depth distribution and empirical scaling laws. This model is our preferred initial stress state and frictional property settings for earthquake modelling of the Hikurangi–Kermadec subduction interface. Introducing heterogeneity of other parameters within RSQSim (e.g. friction coefficient, reference slip rate, characteristic distance, initial state variable, etc.) could further improve the applicability of the synthetic earthquake catalogues to seismic hazard problems and form the focus of future research.
Lexical Language Contact Phenomena: A Combined Model Based on the Vocabulario español-guarani (18th century)
Authors: Gimeno María Cecilia , Stala Ewa
Published: August 2024

The purpose of this work, which falls within the areas of lexicography (studying missionary linguistics) and sociolinguistics (studying cultural contact), is to analyse the linguistic and cultural contacts between Spanish and Guarani, based on lexicographic material extracted from the Vocabulario español-guarani by Pablo Restivo (1728). The basis of the analysis is provided by the names of animals—one of the ‘secular’ fields where the highest frequency of borrowings is found (Cerno & Obermeier 2013). The methodology applied is the Haspelmath model (2009) and the Gruda model (2018). The premise is that the arrival and work of the Jesuit missionaries created cultural contact that is reflected in the codified language and, in turn, in this dictionary of the time. The main contribution is a new combined model of lexical reflections in a situation of cultural contact that can be applied in the analysis of this kind of lexicographic work, while an additional section provides a presentation of Restivo’s work and its background.
Modification of carbapenemase inhibition test and comparison of its performance with NG-Test CARBA 5 for detection of carbapenemase-producing Enterobacterales
Authors: Wang Yue , Huang Xiangning , Yin Dandan , Shen Siquan , Jian Cui , Sun Ziyong , Hu Fupin , Yu Hua , Chen Zhongju
Published: August 2024

Aims

Adequately and accurately identifying carbapenemase-producing Enterobacterales (CPE) is vital for selecting appropriate antimicrobial therapy and implementing effective infection control measures. This study aims to optimize the phenotypic detection method of carbapenemase for routine diagnostics in clinical microbiology laboratories.

Methods and Results

Carbapenemase genes in 2665 non-duplicate CRE clinical strains collected from various regions of China were confirmed through whole-genome sequencing (WGS). The carbapenemase inhibition test (CIT) was conducted and interpreted using different methods and breakpoints, then compared with the NG-Test CARBA 5 for carbapenemase detection. The diagnostic performance of the CIT method was optimal when the carbapenemase types were determined by comparing the inhibition zone diameters of the imipenem disc with 3-aminophenylboronic acid (APB) plus ethylenediaminetetraacetic acid (EDTA) to those of the imipenem disc with either APB or EDTA alone, with a breakpoint of 4 mm. The overall sensitivities of the current CIT, the modified CIT, and NG-Test CARBA 5 were 91.4%, 94.9%, and 99.9%, respectively. For detecting isolates co-producing Klebsiella pneumoniae carbapenemase (KPC) and metallo-β-lactamases (MBLs), the modified CIT method had higher sensitivity than the current method (70.0% vs. 53.3%), though this difference was not statistically significant (P = 0.063). The NG-Test CARBA 5 showed excellent performance for multi-carbapenemases diagnosis, with sensitivity and specificity of 97.1% and 100%, respectively.

Conclusions

Optimizing and standardizing the CIT method for clinical use is necessary. It has certain advantages in diagnosing multi-carbapenemase and rare carbapenemase production. However, for identifying common carbapenemase types, the NG-Test CARBA 5 demonstrated superior performance.
Effects of a liquid and dry Saccharomyces cerevisiae fermentation product feeding program on ruminal fermentation, total tract digestibility, and plasma metabolome of Holstein steers receiving a grain-based diet
Authors: Odunfa Oluwaseun A , Dhungana Anjan , Huang Zhengyan , Yoon Ilkyu , Jiang Yun
Published: August 2024

The study aimed to determine the effects of a postbiotic feeding program consisting of liquid and dry Saccharomyces cerevisiae fermentation product (SCFP) on ruminal fermentation, digestibility, and plasma metabolome of Holstein steers receiving a grain-based diet. Eight Holstein steers (body weight, BW, 467 ± 13.9 kg) equipped with rumen cannulas were used in a crossover design study, with 21 d per period and a 7-d washout period in between periods. Steers were stratified by initial BW and assigned to 1 of 2 treatments. The treatments were 1) Control, basal finishing diet only (CON); 2) SCFP, 1-d feeding of liquid SCFP (infused into the rumen via the cannula at 11 mL/100 kg BW) followed by daily feeding of dry SCFP (12 g/d, top-dressed). Feed and spot fecal samples were collected during days 17 to 20 for determination of digestibility and fecal excretion of N, P, Cu, and Zn. Digestibility was measured using acid-insoluble ash as an internal marker. Blood samples were collected on day 21 before the morning feeding. Rumen fluid samples were collected on days 0, 1, 2, 3, 5, and 21 via rumen cannula. Results were analyzed with the GLIMMIX procedure of SAS 9.4 (SAS, 2023). Treatment did not affect dry matter intake (P = 0.15) and digestibility (P ≥ 0.62). The fecal output and absorption of Zn, Cu, P, and N were not affected (P > 0.22) by treatment. On day 1, the liquid SCFP supplementation tended to reduce (P = 0.07) ruminal VFA concentration and increased (P < 0.01) the molar proportion of valerate. Feeding SCFP tended to increase total ruminal VFA on day 5 (P = 0.08) and significantly increased total VFA on day 21 (P = 0.05). Ruminal NH3–N was reduced (P = 0.02) on day 21 by supplementing SCFP. Treatment did not affect the production of proinflammatory cytokines, interleukin (IL)-1β (P > 0.19), and IL-6 (P > 0.12) in the whole blood in response to various toll-like receptor stimulants in vitro. Feeding SCFP enriched (P ≤ 0.05) plasma metabolic pathways, including citric acid cycle, pyrimidine metabolism, glycolysis/gluconeogenesis, retinol metabolism, and inositol phosphate metabolism pathways. In summary, supplementing liquid SCFP with subsequent dry SCFP enhanced ruminal total VFA production and reduced NH3–N concentration in the rumen. Furthermore, feeding SCFP enriched several important pathways in lipid, protein, and glucose metabolism, which may improve feed efficiency of energy and protein in Holstein steers.
Making the most of canopy light: shade avoidance under a fluctuating spectrum and irradiance
Authors: Sellaro Romina , Durand Maxime , Aphalo Pedro J , Casal Jorge J
Published: August 2024

In the field, plants face constantly changing light conditions caused by both atmospheric effects and neighbouring vegetation. This interplay creates a complex, fluctuating light environment within plant canopies. Shade-intolerant species rely on light cues from competitors to trigger shade avoidance responses, ensuring access to light for photosynthesis. While research often uses controlled growth chambers with steady light to study shade avoidance responses, the influence of light fluctuations in real-world settings remains unclear. This review examines the dynamic light environments found in woodlands, grasslands, and crops. We explore how plants respond to some fluctuations but not others, analyse the potential reasons for these differences, and discuss the possible molecular mechanisms regulating this sensitivity. We propose that studying shade avoidance responses under fluctuating light conditions offers a valuable tool to explore the intricate regulatory network behind them.
3D aeronomy of two mini-neptunes in the HD 63433 system and their in-transit absorption in Ly α and metastable He i lines
Authors: Berezutsky A G , Shaikhislamov I F , Rumenskikh M S , Miroshnichenko I B , Khodachenko M  L , Golubovskii M P , Sharipov S S
Published: August 2024

The numerical simulation of the HD 63433 system is performed with the aim to study upper atmospheres of two mini-Neptunes, planets b and c, interacting with the stellar wind of the parent star. The obtained results demonstrate that both exoplanets form the extended envelopes with strong supersonic outflows. The synthetic absorption profiles in the Ly α line show that under moderate stellar wind conditions, similar to those of the normal solar wind, the energetic neutral atoms contribute to the absorption in the high-velocity blue wing of the line at a level of tens per cent. The absorption in metastable helium He i(23S) line appears rather weak and below the detection limit by current instruments. An important feature revealed by the simulations is that the tail of escaping atmospheric material of the inner planet disturbs the stellar wind at orbital location of the outer planet and might, therefore, affect its observation in Ly α line.
BSBM-11 NEUROCOGNITIVE OUTCOMES OF HIPPOCAMPUS-SPARING WHOLE-BRAIN RADIATION THERAPY VERSUS WHOLE-BRAIN RADIATION THERAPY IN PATIENTS WITH BRAIN METASTASIS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Salman Afia , Naeem Unaiza , Ghazanfar Shamas , Jawed Areesha , Farooq Minaam
Published: August 2024

INTRODUCTION

Whole brain radiation therapy (WBRT) is administered both prophylactically and therapeutically in patients with suspected and confirmed brain metastasis. Despite effective intracerebral tumor control and reduction in neurological mortality, WBRT is associated with a substantial risk of cognitive decline. Hippocampus-sparing WBRT (HS-WBRT) allows for the preservation of memory and other cognitive functions. We aimed to evaluate the neurocognitive outcomes of HS-WBRT in comparison with WBRT in patients with brain metastases.

METHODS

We searched MEDLINE (PubMed), Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for cohort studies and clinical trials reporting on HS-WBRT compared to WBRT for neurocognitive outcomes in brain metastasis patients, from inception to March 2024. Studies that were published in non-English language(s) and/or did not report neurocognitive outcomes of HS-WBRT compared with WBRT were excluded. Summary data of the eligible studies was extracted, which was analyzed for neurocognitive function testing.

RESULTS

Of the total nine studies, seven were included in the quantitative analysis. HS-WBRT led to a statistically significant reduction in cognitive decline as measured by the Hopkins Verbal Learning Test (HVLT) raw scores for total recall (TR) [SMD = 0.34 [0.16,0.53]; I2= 65%; p = 0.0003], and delayed recall (DR) [SMD = 0.26 [0.13,0.39]; I2= 62%; p = 0.0001]. Cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), was also lower in the HS-WBRT group compared to the WBRT group [SMD = 0.82 [0.53,1.10]; I2= 88%; p < 0.00001].

CONCLUSION

The findings of our study demonstrate that HS-WBRT confers a therapeutic advantage to WBRT in improving neurocognitive outcomes for patients with brain metastasis as measured by scores on HVLT-TR, HVLT-DR, and MoCA. Additional studies analyzing both treatment modalities’ adverse effects and mean survival time are imperative for informing future clinical recommendations.
BSLM-05 TRASTUZUMAB DERUXTECAN IN LEPTOMENINGEAL METASTASES FROM HER2-ALTERED CANCERS
Authors: Cao Toni , Roy-O’Reilly Meaghan , Yao Lilian , Ma Qian , Xu Nova , Nagpal Seema , Rogawski David
Published: August 2024

Emerging data suggest that trastuzumab deruxtecan (T-DXd) is a clinically active treatment for brain metastases from HER2+ breast cancer. We aimed to characterize the activity of T-DXd in the treatment of leptomeningeal metastases (LM) from a range of HER2-altered cancers. We reviewed neuro-oncology clinic records between July 2020 and December 2023 to identify patients who received T-DXd to treat LM. Out of 14 patients, 5 had HER2+ breast cancer, 5 had HER2-low breast cancer, 2 had HER2+ gastroesophageal cancer, and 2 had HER2-mutant non-small cell lung cancer. 8/14 (57%) patients had LM diagnosis confirmed with cancer cells in CSF found by cytology or circulating tumor cell (CTC) capture. 4/5 (80%) patients with HER2+ breast LM had a partial response on MRI using the EORTC/RANO-LM Revised-Scorecard. In contrast, 0/9 (0%) patients with other tumor pathologies had radiologic response of their LM to T-DXd. Median survival of the 5 patients with HER2+ breast cancer after initiating T-DXd was 13.9 months with 2 patients alive and continuing on T-DXd at data cutoff, whereas median survival of the 9 patients with other pathologies was 4.1 months (HR 0.32, 95% CI 0.097-1.0, p=0.05). Our findings agree with other retrospective studies showing clinical activity of T-DXd in HER2+ breast LM, but caution that T-DXd may be less effective in LM caused by HER2-low breast and other HER2-altered cancers. Given the small number of patients in our study, larger prospective studies are urgently needed to better delineate which LM patients benefit from T-DXd.
BSLM-09 IDENTIFICATION OF DRUGS WITH SELECTIVE ACTIVITY AGAINST MELANOMA-ASSOCIATED LEPTOMENINGEAL DISEASE USING PATIENT-DERIVED CIRCULATING TUMOR CELLS
Authors: Law Vincent , Bayle Simon , Duckett Derek , Forsyth Peter
Published: August 2024

BACKGROUND

Melanoma associated leptomeningeal disease (M-LMD) occurs in ~5% of late stage melanoma patients and the prognosis is dismal without effective treatments. The difficulty in obtaining enough patient-derived cerebral spinal fluid-circulating tumor cells (PD-CSF-CTCs) and the absence of model systems to study the biology of M-LMD have posed challenges in assessing novel therapeutics. To address this, we have made considerable progress in routinely collecting CSF and tissue specimens (in clinic and at rapid autopsy). Recently, we successfully propagated CSF-CTCs from patients in vitro and in murine xenograft models. With these tools and -omics techniques we found unique M-LMD-specific biological pathways. In the current preliminary study, we identified clinical compounds that could target these biological pathways and have efficacy against PD-CSF-CTCs in vitro and in vivo.

METHODS

PD-CSF-CTCs were derived and propagated from individual M-LMD patients. Next, a 384-well high throughput cell-based process was developed to screen a library of more than 1,400 FDA-approved small molecule compounds to identify pharmaceutics that inhibit cell proliferation. Clinical compounds with the highest sensitivity were selected for validation of efficacy in vivo via intrathecal (IT) delivery of patient-derived cell lines to establish M-LMD xenografts.

RESULTS

Of the 1,436 FDA-approved small molecule compounds, 57 (~3.9%) exerted 95% proliferation inhibition and 20 (~1.4%) had 100% killing effect in PD-CSF-CTCs and murine melanoma cell lines. The compounds with the highest sensitivity include ponatinib (EC50: 1.85 – 4.06e-06), sorafenib (EC50: 9.57 – 9.77e-06), ceritinib (EC50: 1.84 – 2.05e-06) and homoharringtonine (HHT) (3.63 – 4.11e-08). In a randomized murine M-LMD efficacy study, we selected the HHT compound which was given by systemic or intrathecal (IT) injections and found M-LMD mice that received a daily IT dose of 14.5ng HHT resulted prolonged median survival (control vs. HHT, P value: 0.0006; Mantel Cox test).

CONCLUSION

This is the first demonstration of an approach that allows for the rational development of therapeutics in M-LMD, which may help identify drug candidates for future trials.
BMRK-06 BRAIN METASTASIS FREE SURVIVAL OF HER2 LOW AND HER2 ZERO TRIPLE NEGATIVE METASTATIC BREAST CANCER: A WILMOT CANCER INSTITUTE EXPERIENCE (THE HERZELO-TNBC STUDY)
Authors: Evans William , Strawderman Myla , Zhang Huina , O’Regan Ruth , Hicks David , Dhakal Ajay
Published: August 2024

BACKGROUND

It is unclear if level of HER2 expression in metastasis triple negative breast cancer (mTNBC) affects risk of CNS metastasis (CNS-failure). Objective: to compare risk of CNS-failure between HER2-Low [immunohistochemistry 2+ (with ISH-negative) or 1+) and HER2-Zero (immunohistochemistry 0) mTNBC.

METHOD

This is a single-institution retrospective study of mTNBC diagnosed January 2010-January 2022. CNS metastasis at the time of mTNBC diagnosis were excluded. Overall survival (OS) and cause-specific risk of CNS-failure was described using Kaplan-Meier method stratified by HER2 status and compared using log-rank test. A multivariate Cox model was used to estimate hazard ratio (HR) for OS and cause-specific CNS-failure. Because death prior to CNS-failure is a competing-risk, cumulative incidence of CNS failure by HER2 status was estimated and compared using Gray’s test. To adjust for other covariates, Fine-Gray model was used to estimate sub-distribution hazard. Significance level for this study was 10%. HRs were reported with 90% confidence intervals (CI).

RESULTS

As of August 2023, 31 CNS-failures and 68 deaths were observed among 86 patients (57 HER2-Low, 29 HER2-Zero) enrolled. Baseline variables were similar in 2 groups except a higher proportion of bone metastasis in HER2-Low group (62% vs 42%, p=0.08). OS was not different between 2 groups in an unadjusted analysis [median(mo): HER2-Low=15.9 vs HER2-Zero =17.8, p=0.51], and in Cox model (HR=1.12, 90%CI=0.72-1.73, p=0.68). Cause-Specific analysis: HER2-Low group had shorter time to CNS-failure in unadjusted [median(mo): HER2-Low=22.0 vs HER2-Zero =33.4, p=0.082] and in Cox model (HR=2.29, 90%CI=1.20-4.37, p=0.035). Competing-Risk analysis: HER2-Low group had higher cumulative risk of CNS-failure in unadjusted analysis [median(mo): HER2-Low=34.5 vs HER2-Zero =not reached, p=0.049] and in Fine-Gray model (HR=2.69, 90%CI=1.42-5.12, p=0.011).

CONCLUSION

This single-institution study shows a higher risk of CNS-failure in HER2-Low compared to HER2-Zero mTNBC, even after accounting for death as competing risk.
BMRK-13 CSF TUMOR CELL (CSF-TC) DETECTION, QUANTIFICATION AND BIOMARKER ASSESSMENT HELPS IN CLINICAL MANAGEMENT OF BREAST CANCER AND NON-SMALL CELL LUNG CANCER PATIENTS HAVING LEPTOMENINGEAL DISEASE (FORESEE STUDY, NCT05414123)
Authors: Kumthekar Priya , Youssef Michael , Yang Jonathan , Piccioni David , Beruti Sue , Gillis Laura , Gordon Kelly , Blouw Barbara , Moore Melissa , LaFrance Norman , Hedrick Marc , Nagpal Seema
Published: August 2024

Leptomeningeal metastases (LM) in solid tumors is difficult to diagnose and treat, and occurs when there are cancer cells in the cerebrospinal fluid (CSF)/pia and arachnoid. Current standard of care methods to diagnose or assess treatment response of LM (Clinical Evaluation, MRI and Cytology) have limited sensitivity and specificity. This creates challenges for physicians to manage LM or determine the best course of treatment. The FORESEE Study was a multi-center, prospective clinical trial evaluating a novel diagnostic platform, CNSide, that aimed to overcome these challenges. The FORESEE study enrolled patients with breast or non-Small Cell Lung Cancer (NSCLC) with suspicion of or confirmed LM. CNSide can detect and quantify tumor cells in the CSF from patients with breast cancer or NSCLC having a suspicious or confirmed LM as well as identify actionable mutations in the CSF via Fluorescent In Situ Hybridization (FISH) and next-generation sequencing. The primary end point was to determine the impact of CNSide on physician treatment decisions. Secondary endpoints included evaluating the clinical performance of CNSide vs. cytology in tumor cell detection (sensitivity, specificity, PPV and NPV). The study enrolled 40 patients (22 breast cancer and 19 NSCLC). Each patient underwent standard of care diagnostic evaluations at baseline and at three follow up timepoints through their treatment. CNSide aided clinical decision making in 93% (50/54) of the clinical decisions. At baseline, 39 patients were assessed, showing that CNSide confirmed a positive LM diagnosis in 15% (6/39), a negative LM diagnosis in 8% (3/39), progression in 15% (6/39), resolution in 15% (6/39) and no progression, or resolution in 36% (14/39) of the patients. CNSide informed the specific drug selected for treatment in 26% (10/39) patients at baseline and demonstrated clinical high utility. The FORESEE data is undergoing ongoing analysis; full analysis will be presented at the meeting.
DSAI-02 AN AUTOMATED TRAJECTORY OPTIMIZATION ALGORITHM FOR LASER INDUCED THERMAL THERAPY (LITT) FOR BRAIN TUMORS
Authors: Lu Yonggang , Krucoff Max
Published: August 2024

PURPOSE

To plan laser probe trajectories for magnetic resonance imaging (MRI)-guided laser induced thermal therapy (MRIgLITT), current clinical practice relies on manual inspection on MRI images to find a path with minimum safety risk and maximal treatment impact. This process is empirical and time-consuming with potentially suboptimal solutions. The study aims to develop an automated trajectory optimization algorithm for reducing planning time and improving patient safety.

METHODS

Seven brain tumor cases treated with MRIgLITT were retrospectively reviewed. For each case, preoperative MRIs were auto-segmented for 16 brain tissue types (e.g., skull, artery, vein, etc.) using a deep learning-based head modeling algorithm (Sim4life v8.0, ZMT Zurich MedTech AG, Switzerland); Then an optimize trajectory was generated by searching potential trajectories based on a priori established criteria, such as trajectory feasibility (angle to the skull, not entering in the face or neck, etc.), safety risk (avoiding blood vessels and optical cranial nerves, etc.), and expected treatment efficacy (100% tumor coverage with assumed 1.5 cm laser radiation radius). The predicted optimal trajectories were finally compared with the trajectories prescribed from clinical procedures, and differences were analyzed descriptively.

RESULTS

For each case, the algorithm took approximately 4 minutes for brain tissue segmentation and 2 minutes for trajectory optimization on a desktop computer. The predicted trajectories from 7 cases were visually matched with prescribed trajectories with offsets of entry point (9.94±5.97 mm), target point (4.59±2.23 mm) and trajectory length (5.90±3.69 mm). Qualitative review of these trajectories confirmed their adherence to the above principles, meaning they would likely have been usable for their respective cases.

CONCLUSION

We demonstrated the feasibility and efficiency of an automated trajectory optimization algorithm for MRIgLITT. Future studies will improve the performance of brain tissue segmentation, assess anticipated versus achieved tissue treatment volumes, and prospectively evaluate application into case planning.
IMUN-04 COMBINING CHECKPOINT BLOCKADE AND LASER ABLATION FOR PROGRESSIVE NON-SMALL CELL LUNG CANCER BRAIN METASTASES
Authors: Haskell-Mendoza Aden , Srinivasan Ethan , Gonzalez Ariel , Reason Ellery , Jackson Joshua , Wachsmuth Lucas , Lerner Emily , Underwood Delaney , Buckley Evan , Zaidi Saif , II James Herndon , Fecci Peter
Published: August 2024

BACKGROUND

Laser interstitial thermal therapy (LITT) is a minimally invasive surgical treatment being employed frequently for radiographically progressive brain metastases (BM). Considerable interest exists in combining LITT-mediated in situ vaccination to license immune checkpoint blockade (ICB) and activate an anti-tumor immune response. However, LITT also disrupts the blood-brain barrier, causing transient peritumoral edema. Accordingly, information on safety and feasibility of this combination in BM is needed.

METHODS

All patients receiving LITT for radiographically progressive non-small cell lung carcinoma (NSCLC) BM at a single center from 2015 – 2023 were retrospectively reviewed. Combination therapy was defined as ICB within 6 weeks of LITT. Clinical data, post-LITT freedom from local progression (FFLP), and overall survival (OS) were collected. Adverse events (AEs) were evaluated according to Common Terminology Criteria.

RESULTS

Eighteen patients received LITT + ICB to a total of 19 lesions. Median time between therapies was 2.29 weeks (range 0.85 – 5.98). In comparison to NSCLC patients receiving LITT alone (n = 25), there was no decrement in % ablation (98 vs 95%, P = 0.1), length of stay (1 vs 1 days, P = 0.91), home discharge (100 vs 92%, P = 0.5), or 30-day readmissions (15.8 vs 16%, P = 0.99). Despite decreased preoperative steroid use (P = 0.0098), patients receiving LITT + ICB discontinued steroids at a median of 11 (4 – 147) days post-LITT vs. 24 (3 – 242) days for patients receiving LITT alone (P = 0.62). At study cutoff, 18/19 (94.7%) lesions in the LITT + ICB group and 22/25 (88.0%) in the LITT only group were locally controlled. There were 3 and 5 AEs ≥ Grade 3 in the LITT + ICB and LITT alone group, respectively.

CONCLUSIONS

Combination LITT and ICB does not compromise procedural outcomes and may favorably impact local control in NSCLC. Prospective studies are needed to assess biomarkers of immune response.
MMOD-03 CRANIOTOMY RATES FOR BRAIN METASTASES AFTER INTRODUCTION OF IMMUNOTHERAPY
Authors: Pelcher Isabelle , Begley Sabrina , Sreenivasan Sanjeev , Ziemba Yonah , Travaglia Isabella , Ratra Avi , Schulder Michael
Published: August 2024

Immunotherapy has been found effective for many patients with solid tissue cancers, with long-term remission of systemic disease and even of brain metastases from these treatments alone. We sought to determine whether the rates of craniotomies have changed since the introduction of immunotherapy. Institutional data of brain metastases incidence was gathered from 2011-2022 and included demographics and primary cancer information. A total of 885 samples from 789 unique patients were analyzed. National data were queried from the NSQIP database from 2011-2022 to include patients surgically treated for brain metastases for a total sample of 14,494 cases. A Craniotomy for Metastasis Index (CMI) was calculated and plotted over time. The most common institutional primary cancers were lung (46.1%), breast (17.4%), and gastrointestinal (10.1%) cancer. The most common lung cancer subtype was adenocarcinoma (57.11%) followed by non-small cell lung cancer (NSCLC) (11.52%). Institutionally, the CMI showed a non-significant decrease in craniotomies (R2=0.0545, p=0.46). When comparing the institutional CMI between 2011-2016 and 2017-2022, there was no significant change (p=0.37). Nationally, the CMI had a significantly positive slope of 0.03 (R2=0.544, p=0.006). When comparing the national CMI between 2011-2016 and 2017-2022, there was a significant increase in craniotomies (p=0.005). Despite the increasing efficacy of immunotherapy in the treatment of patients with brain metastases, the number of craniotomies remained constant institutionally and increased nationally. Possible explanations for these findings include improved surgical techniques that have made resection safer, along with longer survival of patients with systemic cancer who then develop metastatic brain tumors.
MMOD-06 IMPACT OF SYSTEMIC THERAPY TIMING AFTER STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN-ONLY METASTASES
Authors: Qazi Jamiluddin , Carpenter David , Broadwater Gloria , Van Swearingen Aamanda , Lent Jim , Arshad Muzamil , Chmura Steven , Bansal Rani , Fecci Peter , Kirkpatrick John , Alder Laura , Salama Joseph , Floyd Scott , Mullikin Trey , Anders Carey
Published: August 2024

The impact of systemic therapy (ST) on outcomes for patients with brain-only recurrence in the absence of extracranial disease (ECD) is not well established. We compared outcomes between patients with brain-only metastases (BrM) treated with stereotactic radiosurgery (SRS) who received ST ≤3 months (mos), >3mos, or not at all after SRS. We identified patients completing a course of SRS, without ECD, across two institutions from 1/2015-12/2020. Intracranial progression after SRS was determined by radiographic recurrence on brain MRI. Overall survival (OS) and intracranial progression free survival (iPFS) estimates were generated via the Kaplan-Meier method. 342 pts with brain only metastases were identified. Primary sites included lung (73%), breast (12%), and additional sites (15%) including melanoma/skin, genitourinary, gastrointestinal, head/neck, and other/unknown. Almost half, 169 (49%), received no ST, 80 (23%) received ST ≤3mos, and 93 (27%) received ST >3mos after SRS. Median age was younger in the ST >3mos cohort (60.5yo versus overall median age 65.3yo, p=0.0002). Performance status, race, and gender were not significantly different between groups. Median OS differed significantly between groups: ST ≤3mos with 24.9mos (95%CI: 16.6-51.1), ST >3mos with 27.9mos (95% CI: 20.6-37.5), and no ST after SRS with 11.0mos (95%CI: 8.9-17.5), p=0.002. Median iPFS differed significantly between groups: ST ≤3mos with 16.1mos (95% CI: 16.1-33.7), ST >3mos with 8.9mos (95% CI: 6.9 – 13.5), and no ST after SRS with 10.0mos (95% CI: 6.7- 15.1). However, iPFS was non-significant in multivariate analysis adjusting for age, performance status, metastatic burden, tumor type, and prior ST. In a multi-institutional cohort of patients with BrM, ST after SRS improves OS regardless of timing. Additionally, ST ≤3mos appears to improve iPFS compared to ST >3mos after SRS, which warrants further investigation. Appropriate patients with BrM should be routinely referred for a multi-disciplinary discussion of systemic therapy following SRS.
MMOD-08 REAL WORLD TREATMENT PATTERNS AND OUTCOMES FOR PATIENTS WITH MELANOMA BRAIN METASTASIS: A SINGLE CENTER EXPERIENCE
Authors: Ladwa Amrita , Elghawy Omar , Friedberg Jacob , Kaur Varinder
Published: August 2024

BACKGROUND

Traditionally, patients with melanoma brain metastasis (MBM) have poor survival outcomes. We investigated real-world treatment patterns and outcomes of patients with MBM.

METHODS

We conducted a retrospective, single-institution analysis of patients with malignant melanoma who received immunotherapy and developed synchronous or metachronous MBM. Real world treatment patterns, therapy sequencing and outcomes were analyzed in detail.

RESULTS

Of 453 patients with melanoma who received immunotherapy at our center, 138 developed brain metastases. Median age was 59 years, 63% were male, and 91% were white. 72% had cutaneous melanoma, 5% had mucosal, 4% had acral, and 19% had other subtypes. BRAF V600 mutation was positive in 36%. 44% had synchronous MBMs (within 30 days of diagnosis of unresectable/metastatic disease), and 56% had metachronous MBMs. 3% had solitary MBMs without concurrent extracranial disease. For patients with metachronous MBMs, median time to CNS metastasis from stage IV diagnosis was 11 months (range, 1 – 211 months). 69% of patients had 1 – 5 MBMs, 20% had 6 – 10 MBMs, and 11% had 11 or more MBMs. For first-line therapy, 66% received stereotactic radiosurgery (SRS) or gamma-knife radiosurgery (GKRS), 14% underwent surgical resection, 12% received whole-brain radiation therapy (WBRT), 88% received systemic therapy (with or without other therapy), and 72% received systemic therapy and loco-regional therapy. Systemic therapies included ipilimumab/nivolumab (36%), nivolumab alone (10%), pemboliaumab alone (20%), ipilimumab alone (23%), BRAF/MEKi (6%), or other (11%). 54% of patients who received treatment and/or were followed with imaging experienced disease progression. Median overall survival (OS) for the entire cohort was 66 months (range, 1 – 407 months).

CONCLUSION

Most patients with MBM receive a combination of loco-regional interventions and systemic therapy. Real-world outcomes for patients with MBMs have improved with newer treatments.
MMOD-12 PATHOLOGIC INCIDENCE OF TUMOR POSITIVITY VS ONLY NECROSIS AFTER PRIOR RADIATION IN PATIENTS UNDERGOING SURGICAL EXCISION FOR PRESUMED BRAIN METASTASIS RECURRENCE: INSIGHT FROM A PROSPECTIVE MULTICENTER REGISTRY
Authors: Kotecha Rupesh , McDermott Michael , Lee Stuart , Peach Matthew , Richardson Angela , Floyd John , Patel Toral , Wardak Zabi , Sloan Lindsey , Ferreira Clara , Neil Elizabeth , Hunt Matthew , Shen Colette , Wasilewski Andrea , Wanebo John , Smith Kris , Chamoun Roukoz , Robin Adam , Lee Ian , Leng Lewis , Patel Akash , Zhu James , Hanft Simon , Zeller Sabrina , Aizenberg Michelle , Rodriguez Analiz , Choutka Ondrej , Hoang Kimberly , Nowlan Adam , McCracken David , Dunbar Erin , Brachman David , Garcia Michael , Patel Sita
Published: August 2024

PURPOSE/OBJECTIVE(S)

Determining true recurrence versus necrosis alone after previous radiation therapy (RT) for brain metastasis based on imaging alone is difficult. Proper diagnosis is essential, as further radiation is contraindicated in the setting of radiation necrosis without tumor (TUM-). To better understand the rate of pathologic tumor positivity (TUM+) vs TUM-, we examined frozen section results from a cohort of patients with prior same-site RT undergoing resection of presumed recurrent brain metastasis (RBM).

MATERIALS/METHODS

Rates of intraoperative frozen section pathology disclosing tumor +/- necrosis (TUM+) or necrosis without tumor (TUM-) were examined in patients undergoing resection for presumed RBM after prior same-site RT. All cases had been prospectively enrolled on a multi-institution registry for patients undergoing resection and intraoperative cesium-131 collagen tile brachytherapy (NCT04427384)(GammaTile, GT Medical Technologies, Tempe AZ, USA). Preoperative evaluation varied by center, and patient demographics, primary site, lesion size, and prior therapies were also examined.

RESULTS

From 10/2020 to 2/2024 60 patients (64 lesions) underwent resection and intraoperative frozen section pathologic evaluation. Per patient, primary sites were 53% lung, 15% melanoma, 13% breast, 7% renal, and 10% other. F:M ratio was 31:29; median age 62, maximum preoperative diameter 2.9 cm, and median time from prior RT 15.4 months. Across all histologies TUM+ was seen in 88% (53/60) and TUM- in 12% (7/60). Rates of TUM- by primary type were highest for lung (16%), breast (13%), and melanoma (11%). The TUM- rate for lung metastasis was 16% vs 7% for non-lung origin. All TUM- patients received RT and prior chemotherapy, immunotherapy, or both.

CONCLUSION

For all previously irradiated metastasis, pathology demonstrated a 12% rate of TUM-. As all cases necessitated surgery, the adverse event grading would be ≥ Gr 4. These findings highlight the importance of pathologic confirmation before undertaking re-irradiation for presumed radiographic recurrence.
NIRL-09 PERI-AMPULLARY CARCINOMA METASTASIS TO THE BRAIN: A RARE CASE REPORT FROM INDIA
Authors: Sangwan Arushi , Mishra Saurabh , Rana Shaleen
Published: August 2024

Peri-ampullary carcinoma refers to a group of neoplasms arising from the head of the pancreas, the distal common bile duct (CBD), and the duodenum. It is typically associated with metastases to intra-abdominal sites, distant lymph nodes, lungs, and bone. Metastasis of peri-ampullary carcinoma involving the brain is extremely rare, with less than five reported cases in current literature. We present a case of a 77-year-old male patient, who presented with a two-week history of diffuse abdominal pain and distension associated with post-prandial vomiting. A comprehensive workup involving diagnostic imaging revealed moderate ascites, dilated CBD, splenomegaly, and a heterogeneously enhancing periampullary lesion. Multiple heterogeneously enhancing lesions in the lungs with metastatic features were also seen. Whole body PET-CT showed a hypermetabolic minimally enhancing nodular lesion at the distal CBD. Other lesions with metastatic features were also noted, including multiple retroperitoneal nodes, multiple lung masses, and a hypermetabolic mediastinal node. Bronchoscopy was normal, however, a side-viewing endoscopy biopsy of the peri-ampullary mass confirmed a high-grade malignancy. After counselling the patient at length regarding available treatment options, sphincterectomy and CBD stenting were performed. However, the patient returned after two weeks with confusion, slurring of speech, and worsening abdominal distension. MR imaging demonstrated a heterogeneously enhancing mass in the left frontotemporal region, associated with a disproportionate amount of surrounding edema and mass effect with a significant midline shift. The patient was admitted to the intensive care unit, and the CBD stent was switched with an uncovered self-expandable metallic stent. Unwilling to undergo further treatment, the patient was discharged with scheduled close follow-ups. Though metastasis of peri-ampullary carcinoma to the brain is uncommon, this case highlights the importance of being cognizant of its clinical and radiological features to ensure prompt diagnosis and treatment.
NIRL-14 RADIOGRAPHIC STUDIES ON THE THRESHOLD OF HUMAN CAPACITY IN EARLY DETECTION OF SMALL BRAIN METASTASES ESTABLISH A BASIS FOR DEVELOPING ARTIFICIAL INTELLIGENCE RECOGNITION TECHNOLOGY IN BRAIN MRI
Authors: Zhang Isabella , Burr Justin , Wang Shuo
Published: August 2024

BACKGROUND

Brain Metastases are the most common cancers in central nervous system and carry poor prognosis in cancer patients with their rapidly growing nature. Early identification of these tumors is crucial in improving patient survival. This investigation aims to study the rate of human error in missing early brain metastases and factors associated with the threshold of sensitivity of human eyes at the professional level.

METHODS

The ­database from a single institution was used which included patients with new brain metastasis diagnosed based on brain magnetic resonance imaging (MRI) who also had previous MRI scan(s) 1-6 months before diagnosis and no exposure to whole brain radiotherapy. The brain MRI used for diagnosis of brain metastasis and the MRI performed 1-6 months prior were reviewed. Based on the location of the newly diagnosed tumor, the corresponding location in the previous MRI was assessed for a missed incidence of a preexisting tumor. The sizes of the missed tumors were then measured to assess the threshold of human eyes in detecting metastases.

RESULTS

The percentage of missed metastases was 44% (56/126). The mean size of missed metastases was 3.0 millimeters (range 1.2 mm to 7.7 mm). No clinical factors were significantly associated with higher rate of missed diagnosis. The most likely reason for the missed diagnosis is the tiny size although visual distraction seems to play a role including adjacent contrast-enhancing structures such as blood vessels.

CONCLUSIONS

The results show a high rate of human error for missing small metastases even with high level of expertise indicating the limits of human capacity to reliably detect brain metastases at 1-2 mm in size. These results justify the development of artificial intelligence-based recognition to assist neuroradiologists in diagnosis. Our data support current standard practice of surveillance brain MRI every 3-6 months for patients with history of brain metastasis.
NVTG-03 IDENTIFYING THE DRIVERS OF EARLY BRAIN METASTASES ESTABLISHMENT IN BREAST CANCER PATIENTS
Authors: Ivanova Alyona , Cho Matthew , Wu Megan , Munoz David G , Das Sunit
Published: August 2024

Breast cancer is the most common type of cancer in women. It is also the 2nd most common cause of brain metastases (BrM), with 30-50% of breast cancer patients developing BrM over the course of their disease. Despite aggressive therapy and novel systemic treatment options, prognosis for these patients remains poor. The objectives of our work were to identify the underlying genomic and transcriptomic signatures that characterise early BrM establishment in patients with breast cancer, and to identify brain-intrinsic molecular mechanisms critical to BrM development. We performed transcriptomic and genomic profiling on fresh frozen (FF) brain metastases tumour samples of patients who required surgical resection of an intracranial metastatic early (<3 years from initial diagnosis) or late (>3 years from initial diagnosis) in the disease course. Findings were validated by immunohistochemistry and immunofluorescence staining for genes of interest in BrM, matched primary breast tumour samples, and healthy brain tissue. The findings were complemented with scRNA sequencing studies to resolve cellular contributions of individual cell types and subtypes and uncover specific cell-type interactions in BrM establishment. In patients with early metastatic disease, pathway enrichment analysis identified TGF-β pathway upregulation, which stimulates epithelial-to-mesenchymal transition, integrin-mediated invasion, recruitment and activation of cancer-associated fibroblasts. We identified collagen-extracellular matrix interactions as key oncogenic features of the metastatic tumour microenvironment. We have selected lead candidates that can play significant role in early colonisation of breast cancer cells to the brain from the primary breast tumour and enhance tumorigenesis. These markers will be challenged in an in vivo brain metastasis model to attenuate the establishment of metastatic disease. Our goal is to identify a modifiable marker that could be clinically targeted to prevent the establishment of brain metastases in patients diagnosed with breast cancer.
NVTG-06 MELANOMA BRAIN METASTASES BENEFIT FROM HIGH PRKCZ LEVELS
Authors: Schöne Lisa , Meinhardt Matthias , Mehnert Marie-Christin , Beissert Stefan , Meier Friedegund , Westphal Dana
Published: August 2024

Despite current therapies being proven effective against metastasized melanoma, durable responses against melanoma brain metastases remain pending. The main reasons are brain-specific resistance mechanisms, which motivate investigations into the underlying differences between intracranial and extracranial metastases. While the mutational status is mainly unaltered, epigenetic regulation is diverging. Based on methylome and transcriptome analyses of 16 matched intra- and extracranial metastases, 38 protein candidates with distinct promoter methylation and corresponding expression were identified. Eight promising candidates were validated by immunohistochemistry and had a significantly higher protein expression in intracranial metastases. (PMID: 36716920) In this study, we want to investigate the role of a likely cancer-promoting candidate, named protein kinase C zeta (PRKCz), which is upregulated in intracranial metastases. We found a wide range of PRKCz gene expression in various established as well as in-house patient-derived melanoma cell lines. Cell lines with either high or moderate PRKCz expression were chosen for further functional investigation. Using siRNA-mediated knockdown, a decreased viability was seen in PRKCz-knockdown cells in crystal violet assays. To test their role in migration, a 2D wound closure scratch assay was developed and revealed a decreased wound-closure capacity in PRKCz-knockdown cells. Further, PRKCz was found to regulate phosphorylated AKT, a component of the cancer-promoting PI3K/AKT signaling pathway, while phosphorylated ERK, a MAPK signaling component, remained unaffected. In summary, we have shown that PRKCz promotes cell viability and migration in melanoma cells. Melanoma brain metastases therefore benefit from high PRKCz levels in comparison to lower levels in extracranial metastases.
RADT-02 PRE-OPERATIVE VERSUS POST-OPERATIVE FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 534 RESECTED METASTASES
Authors: Perlow Haley , Hennings Sarah , Bradshaw Jared , Reddy Sohil , Luu Sydney , Matsui Jennifer , Klamer Brett , Dibs Khaled , Harrell Marshall , McGregor John , Lonser Russell , Prevedello Daniel , Elder James , Wu Kyle , Prabhu Roshan , Zhu Simeng , Singh Raj , Beyer Sasha , Grecula John , Blakaj Dukagjin , Thomas Evan , Raval Raju , Palmer Joshua
Published: August 2024

Patients with large or symptomatic brain metastases and limited intracranial disease typically have surgery followed by post-operative (post-op) stereotactic radiosurgery (SRS). However, SRS can lead to elevated rates of radiation necrosis (RN), meningeal disease (MD), and local failure (LF). Fractionated treatments can deliver a higher biological effective dose and may reduce the risk of LF, and pre-operative (pre-op) treatments may reduce the risk of RN and MD through treating smaller volumes and tumor sterilization. We hypothesize that pre-op fractionated stereotactic radiation therapy (FSRT) will reduce the incidence rate of RN, MD, and LF when compared to patients who receive post-op FSRT. A retrospective analysis was performed at a single institution and included patients who had surgical resection and radiation to at least one brain metastasis. Patients with multiple metastases resected, either during the same surgery or at different times in the disease course, were eligible for inclusion. Outcomes were evaluated on a per-lesion basis. The primary outcome was a composite endpoint defined by 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. 458 patients with 534 resected brain metastases were eligible for analysis. 235 metastases received pre-op FSRT, and 299 metastases received post-op FSRT. Overall, 15% of patients had multiple brain metastases resected. Overall, 6 (2.6%) pre-op and 13 (4.3%) post-op patients experienced LF. 21 (8.9%) pre-op and 38 (12.7%) post-op patients experienced symptomatic RN. 11 (4.7%) pre-op and 29 (9.7%) post-op patients were diagnosed with MD (p=0.031). 14% and 24% of metastases that received pre-op and post-op FSRT, respectively, experienced the composite endpoint (p=0.005). In our study, pre-op FSRT compares favorably to post-op FSRT primarily due to a 50% reduction in the incidence of MD. Differences in symptomatic RN or LF were small on adjusted analyses. Prospective validation of pre-op FSRT is needed.