bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arthroscopic treatment of septic arthritis of the ankle joint caused by streptococcus in patients with chronic inflammatory diseases: Two case reports
Authors: Okamura Gensuke , Hirao Makoto , Noguchi Takaaki , Etani Yuki , Ebina Kosuke , Miura Taihei , Tsuboi Hideki , Goshima Atsushi , Okada Seiji , Hashimoto Jun 
Published: August 2024

ABSTRACT
This report describes the arthroscopic treatment of septic arthritis of the ankle joint in two patients with inflammatory diseases, including rheumatoid arthritis and nail psoriasis. We treated both the ankle joints with antibiotic administration and urgent arthroscopic synovectomy and irrigation, although the procedure was performed several days (4 and 6 days) after the time at which the infection would have occurred. Fortunately, no recurrence has been seen for &gt;18 and 20 months, respectively, after surgery, without antibiotic administration. Although septic arthritis of the ankle joint accounts for a small proportion of joint arthritis cases, diagnosis as early as possible is important. Our experience suggests that arthroscopic synovectomy and irrigation are effective for septic ankle arthritis even in chronic inflammatory disease cases.
BSBM-04 THE MULTI-OMIC LANDSCAPE OF SOMATIC VARIATION ACROSS A PAN-CANCER COHORT OF BRAIN METASTASES
Authors: Hall Grace , Campbell Bethany , Stylli Stanley , Jung Chol-Hee , Pope Bernard , Park Daniel , Molania Ramyar , Bedo Justin , Ureta Jennifer , Rodrigues Silvia , Fidalgo-Ribeiro Caroline , Loda Massimo , McCoy Patrick , Gray Clint , Tan Swee , Wickremesekera Agadha , Saunders Christobel , Drummond Kate , Corcoran Niall , Dimou James , Papenfuss Tony , Hovens Christopher 
Published: August 2024

Abstract

INTRODUCTION
Brain metastases pose a significant and growing challenge in clinical practice, yet the molecular variants of this tumor type has not previously been examined comprehensively across multiple cancer types. In particular, there has been limited focus on contrasting the genetic profiles of common brain metastases originating from primary sites like lung, breast, melanoma, colorectal, and renal cancers, with those arising infrequently such as prostate and others.

METHODS
We have prospectively collected over 125 fresh frozen brain metastases and matching germline reference samples from 14 different primary tumor types and to date have performed WGS, RNA-Seq and Epic 850k methylation profiling on 60 of these samples spanning both common and rare brain metastases. We have employed machine learning algorithms, network analysis techniques, and integrative bioinformatics pipelines to extract meaningful insights into the biological underpinnings of brain metastasis formation.

RESULTS
We conducted an in-depth investigation into the genomic, transcriptomic, and epigenomic profiles of brain metastases, spanning both common and rare types. By merging these diverse datasets, we identified distinct molecular modifications linked to brain metastases with low incidence rates compared to those more frequently observed. Notably, we observed heightened alterations in the regulation of Golgi dynamics, sensing of lipid species, chromatin remodeling factors, and cytoskeletal remodeling in rare brain metastases. These changes likely influence cell migration and invasion dynamics, elucidating the potential for unique characteristics of less common brain metastasis types.

CONCLUSIONS
This research indicates that the molecular mechanisms driving the formation of brain metastases may vary depending on whether the primary malignancy frequently or infrequently spreads to the brain. Studies such as these, will aid in eventually driving innovations in precision oncology and ultimately improving patient outcomes.
BSBM-09 ASTROCYTES MEDIATE PARACRINE ACTIVATION OF FGFR1 TO ER+ BREAST CANCER BRAIN METASTASES
Authors: Jaramillo-Gómez Jenny A , Fox Morgan , Cittelly María J Contreras-Zárate Diana M 
Published: August 2024

Abstract
ER+ breast cancer (BC) accounts for ~50% of all BC brain metastases (BCBM) and is severely understudied. By contrast to BM from triple-negative and Her2+ BC, ER+ BCBM occurs mostly in post-menopausal women due to aging or endocrine therapy. Thus, specific interactions with cells within the aged/estrogen-depleted brain tumor microenvironment (TME) may promote ER+ BCBM. Amplification of FGFR1 (a TK receptor that binds canonically to FGF2) is the only genetic alteration shown to predict late recurrence of ER+ BC following anti-estrogen-therapies. Astrocytes promote BM by secreting growth factors that in a paracrine manner activate TK receptors in cancer cells that drive colonization. Thus, we hypothesize that paracrine activation of FGFR1 by astrocytes contributes to estrogen-independent ER+ BCBM outgrowth, and changes in FGFR1 ligand-expression in the brain TME may influence the ability of ER+ BC to colonize the brain niche. Using in vitro co-culture systems, we demonstrate that conditioned media from astrocytes (CMAst) promotes estrogen-independent proliferation and tumor-initiating capability of ER+ FGFR1-amplified PDX-derived cell lines (UCD65). CMAst activated FGFR1 and downstream signaling in ER+ cells, but FGFR1 inhibitors had modest ability to block this signaling, suggesting astrocytes activate FGFR1 dependent and independent pathways. FGFR1 KD impaired the growth of ER+ cells when cultured with CMAst but abolished their growth when co-cultured directly on astrocytes, suggesting FGFR1 is critical for cancer cell-astrocyte direct interactions. Young astrocytes promoted cancer cells proliferation more effectively than aged astrocytes and FGF2 decreased in astrocytes from aged mice compared to young mice, suggesting that FGF2/FGFR1 interactions promote ER+ growth in the young but not the old brain TME. Moreover, ER+ BC cells were able to invade in brain slices from old but not young mice, suggesting that loss of canonical FGF2/FGFR1 signaling (and possibly activation of non-canonical FGFR1 functions) promote metastases in the older brain TME.
BSBM-12 TARGETING OSIMERTINIB-RESISTANT BRAIN METASTASIS USING RAR ANTAGONISTS
Authors: Biswas Anup , Acharyya Swarnali 
Published: August 2024

Abstract
It is estimated that one-third of EGFR-mutant lung cancer patients develop brain metastasis during the course of their disease. Brain metastasis is associated with a significant decline in cognitive and motor function, daily functioning, and accelerated mortality. Brain metastasis is a severe complication for 45% of patients with EGFR-mutant lung cancer that drastically reduces their quality of life and survival. Fortunately, EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib showed excellent blood-brain-barrier permeability and resulted in dramatic responses in patients with brain metastases. However, despite a striking initial response, osimertinib-treated patients eventually develop relapse, often to the brain, and succumb to death. With this fatal malignancy, it is important to understand underlying mechanisms of brain metastasis to improve treatment outcomes, which is an unmet need in the field. To study mechanisms of brain relapse, we generated osimertinib treatment-response-and-relapse mouse models using human lung cancer cells harboring osimertinib-sensitive EGFR-activating mutations. Using these new brain relapse models of EGFR-mutant lung cancer, we identified that a S100A9-ALDH1A1-RA signaling axis endows cancer cells with the ability to thrive in the brain despite on-target inhibition of EGFR activity by osimertinib. Mechanistically, we show that S100A9 upregulates ALDH1A1 expression and activate the retinoic acid (RA) signaling pathway in cancer cells, which promotes brain relapse. We demonstrate that the genetic repression of S100A9, ALDH1A1, or retinoic acid receptor (RAR) in cancer cells, or treatment with a pan-retinoic-acid-receptor antagonist, dramatically reduces brain metastasis in independent preclinical models of brain relapse. Importantly, S100A9 expression in cancer cells correlates with poor PFS in patients on osimertinib. Based on these preclinical findings, we propose that RAR antagonist treatment can be tested in patients to target osimertinib-resistant brain metastases. Notably, intracellular S100A9 expression in cancer cells can be used as a biomarker to stratify patients who might benefit from this combination treatment.
BSBM-16 GLIOBLASTOMA AS A METASTATIC DISEASE: A POSSIBLE MOLECULAR PATHWAY OF METASTATIC SPREAD ACCORDING TO THE GENE MUTATION PROFILE
Authors: Jancalek Radim , Hendyrch Michal , Sana Jiri 
Published: August 2024

Abstract
Glioblastoma (GBM) is the most common glial brain tumor in adults. It accounts for nearly 50 % of malignant primary brain tumors and represents a disease with a dismal prognosis. GBM is characterized by rapid infiltrative spread within the central nervous system; however, its metastases are considered sporadic. The molecular background of primary and secondary GBM is yet to be discovered, making it difficult to describe the possible molecular pathway/s of metastatic spread. Due to increasing overall survival rates in GBM patients, extracranial metastasis is becoming more common, making this topic increasingly relevant. We screened a case of spinal GBM metastasis and its molecular background and searched for differences in gene mutation profile between the primary and metastatic disease to outline possible molecular pathways of metastatic spread. In this study, we discovered that the alteration of NF1, NOTCH3, and ARID1A could explain, at least in part, the acquired invasiveness and metastatic potential in a GBM case. This finding underscores the importance of genetic testing in understanding tumor progression and its potential impact on patient oncological management. The project was supported by the NU23-03-00100 grant from the Ministry of Health, Czech Republic.
BSLM-02 SPATIAL TRANSCRIPTOMICS ANALYSIS IDENTIFIES A UNIQUE TUMOR-PROMOTING FUNCTION OF THE MENINGEAL STROMA IN MELANOMA LEPTOMENINGEAL DISEASE
Authors: Alhaddad Hasan , Ospina Oscar , Khaled Mariam , Ren Yuan , Vallebuona Ethan , Boozo Mohammad Baraa , Forsyth Peter , Pina Yolanda , Macaulay Robert , Law Vincent , Tsai Kenneth , Cress Douglass , Fridley Brooke , Smalley Inna 
Published: August 2024

Abstract
Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. The inaccessible nature of the disease site and lack of understanding of the biology of this unique metastatic site are major barriers to developing efficacious therapies for patients with melanoma LMD. Here, we characterize the tumor microenvironment of the leptomeningeal tissues and patient-matched extra-cranial metastatic sites using spatial transcriptomics analyses in clinical specimens, with extensive in vitro and in vivo validation. We show the spatial landscape of melanoma LMD to be characterized by a lack of immune infiltration and instead exhibit a higher level of stromal involvement. We show that the tumor-stroma interactions at the leptomeninges activate pathways implicated in tumor-promoting signaling, mediated through upregulation of SERPINA3 at the tumor-stroma interface. Our functional experiments establish that the meningeal stroma is required for melanoma cells to survive in the CSF environment and that these interactions lead to a lack of MAPK inhibitor sensitivity in the tumor. We show that knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in re-sensitization of the tumor to MAPK-targeting therapy and tumor cell death in the leptomeningeal environment using in vitro and in vivo models. Our data provides a spatial atlas of melanoma LMD, identifies the tumor-promoting role of meningeal stroma, and demonstrates a mechanism for overcoming microenvironment-mediated drug resistance unique to this metastatic site.
BSLM-03 BRANCHED-CHAIN KETO ACIDS PROMOTE AN IMMUNE-SUPPRESSIVE AND NEURODEGENERATIVE MICROENVIRONMENT IN LEPTOMENINGEAL DISEASE
Authors: Khaled Mariam , Ren Yuan , Kundalia Ronak , Alhaddad Hasan , Chen Zhihua , Wallace Gerald , Evernden Brittany , Ospina Oscar , Hall MacLean , Liu Min , Darville Lancia , Izumi Victoria , Chen Y Ann , Pilon-Thomas Shari , Stewart Paul , Koomen John , Corallo Salvatore , Jain Michael , Robinson Timothy , Locke Fredrick , Forsyth Peter , Smalley Inna 
Published: August 2024

Abstract
Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omic analyses of CSF from patients with melanoma, breast cancer and lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment dominated by inactive, dysfunctional T cells and alternatively activated macrophages. These findings were confirmed in mouse models of LMD. We identified dysregulations in proteins and lipids indicating neurodegenerative processes and reactive gliosis. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. Functionally, BCKA disrupted the viability and function of T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. These findings support the severe neurological decline, deficiency in the anti-tumor immune environment, and lack of response to immune therapies observed in patients clinically. Sodium phenylbutyrate is an FDA-approved BCKA-lowering therapy with exceptional safety profile and CNS penetration. We show that sodium phenylbutyrate improved neurological function and survival outcomes in murine models of breast cancer, lymphoma and melanoma LMD. In lymphoma LMD models, sodium phenylbutyrate also improved the efficacy of CAR T cell therapy. This work provides the preclinical rationale for repurposing BCKA-lowering therapies such as sodium phenylbutyrate for patients with LMD.
BSLM-06 PROGNOSTIC SIGNIFICANCE OF CEREBROSPINAL FLUID GLUCOSE AND PROTEIN LEVELS IN METASTATIC BREAST CANCER PATIENTS WITH LEPTOMENINGEAL DISEASE: A RETROSPECTIVE STUDY
Authors: Niraula Sujan , Gauli Sugam , Baran Andrea M , Tyburski Haley , Zhang Huina , O’Regan Ruth , Mohile Nimish , Anders Carey K , Hardy Sara , Dhakal Ajay 
Published: August 2024

Abstract

BACKGROUND
The prognostic significance of cerebrospinal fluid (CSF) glucose and protein levels among patients with leptomeningeal disease (LMD) is unknown. This single-institution retrospective study aims to investigate the association of CSF glucose and protein levels with overall survival (OS) among metastatic breast cancer (MBC) patients with LMD.

METHODOLOGY
MBC patients diagnosed with LMD between Jan 1st, 2010, and Jan 1st, 2023, were included. Patients without known CSF glucose or protein levels at the time of LMD diagnosis were excluded. OS was evaluated using the Kaplan-Meier method and compared using the log-rank test. For multivariate analysis, a step-wise model selection was performed after the inclusion of sub-type of interest, and variables meeting entry (p&lt;0.10) and staying criteria (p&lt;0.05). Median glucose and protein levels were compared using the Wilcoxon rank-sum test.

RESULTS
28 patients met inclusion criteria. Positive CSF cytology samples (CSF+) had significantly lower glucose levels vs CSF cytology negative samples (CSF-) [median (IQR) 40 (18-58) vs. 64 (53-92) mg/dl, p=0.006]. Prior study from this data set had shown that the CSF- group was associated with better OS vs the CSF+ group. Hence, four groups were created based on the CSF (+/-) and glucose (Low vs High/Normal). Median OS (months), 95% confidence Interval (CI) for CSF+/Glucose_Low, CSF+/Glucose_Normal/High, CSF-/Glucose_Low and CSF-/Glucose_High/Normal were 3.4(0.23-NE), 16.5(2.9-NE), 3.1(1.28-NE), 51.5(4.9-NE), p=0.03. Glucose_Low overall was associated with shorter OS in multivariate analysis [hazard ratio (HR), 95%CI 4.64 (1.71, 13.2)]. Median CSF protein was not different between CSF+/– groups. Median OS (months), 95%CI for Protein_High and Protein_Low /Normal groups were 28.5 (2.9, 51.5) vs. 6.5 (0.85, 8.0), p=0.36. In multivariate analysis, CSF protein level was not associated with OS.

CONCLUSION
The association between low CSF glucose level and worse survival among patients with MBC LMD was observed.
BSLM-07 A FIRST IN HUMAN PHASE 1 TRIAL OF DOSE ESCALATING INTRATHECAL (IT) DENDRITIC CELLS (CDC1S) PRIMED AGAINST HER2/HER3 IN PATIENTS (PTS) WITH LEPTOMENINGEAL DISEASE (LMD) FROM TRIPLE NEGATIVE (TNBC) OR HER2+ BREAST CANCER (BC)
Authors: Forsyth Peter , Gandhi Shipra , Wilcox Jessica , Law Vincent , Mo Qianxing , Chen Zhihua , Ahmed Kamran , Piteo Cecily , Evernden Brittany , Pina Yolanda , Boire Adrienne , Kalinski Pawel , Czerniecki Brian 
Published: August 2024

Abstract

BACKGROUND
Leptomeningeal disease (LMD) is a devastating complication of BC has a dismal prognosis. The CSF of LMD pts have an innate (PMID:34035069), but not adaptive, immune response (bioRxiv 2023.03.17.533041; doi: https://doi.org/10.1101/2023.03.17.533041) that is insufficient to combat LMD. We used IT cDC1 to elicit an adaptive response in LMD and found they were safe, induced a Th1 response, cured most HER2+ LMD, and prevented LMD recurrence (PMCID: 9354231). Responses were CD4+ and B cell dependent. cDC1s induce Th1 responses in HER2/HER3 tumors (PMID: 35710296; PMID: 34785506). And there are trials of cDC1s in BC patients (e.g.NCT03384914, NCT03387553, etc.) We hypothesized that a RP2D would be found and the CSF would be remodeled to have a Th1 immunological profile.

METHODS
Phase I single-arm, dose escalation multicenter study to establish 1) safety of IT cDC1s, and 2) associations between clinical outcomes & translational CSF studies (e.g. scRNAseq, cytokine arrays). Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG ≤2, normal organ function, life expectancy of ≥ 8 weeks, and an Ommaya. IT cDC1s were administered weekly x 12 wks at one of 4 dose levels (1 X 106 – 5 X 107 cDC1s) until PD, DLT or withdrawal. Primary Endpoints were 1) safety and DLTs, 2) association between clinical endpoints and immune profiles. We used the BOIN design for the MTD. Response was measured using RANO-LM (PMID: 30715514). DLTs were defined as ≥ gr. 3 not due to LMD, resistant to medical intervention/CSF removal. Final pre & post cDC1 treatment cyto/chemokine & scRNAseq will be determined. As of 04 01 2024, 4 pts were treated [3 pts cohort 1 @ 1 X 106 & 1 pt cohort 2 @ 2 X 106]. NCT05809752. Sponsor: Department of Defense
BMRK-01 EXTERNALLY VALIDATED PREDICTIVE NOMOGRAM FOR BRAIN METASTASIS IN EARLY-STAGE BREAST CANCER
Authors: Jennings Kristofer , Raghavendra Akshara Singareeka , Kotecki Nuria , Amato Ottavia , Tripathy Debu , Awada Ahmad , Ibrahim Nuhad 
Published: August 2024

Abstract

BACKGROUND
Brain metastasis presents a significant concern for early-stage breast cancer (ESBC) patients, impacting their survival and overall well-being. Constructing a predictive nomogram based on primary tumor characteristics offers a way to anticipate the likelihood of brain metastasis. The objective is to create tools aiding in the identification of high-risk patients, enriching clinical trial cohorts to prevent or delay brain metastasis onset early in the disease.

METHODS
We reviewed 40,290 ESBC cases (stages I-III) at the University of Texas MD Anderson Cancer Center, Houston, spanning January 1, 1997, to May 8, 2020. Validated the model with Institut Jules Bordet, Belgium, patient data for accuracy and reproducibility analyzing 1,644 cases with the same inclusion criteria.Statistical models considered patient age, tumor features (grade, hormone receptor, HER2 status), and treatments (chemotherapy, endocrine therapy). Using these, our multivariate model predicted brain metastasis occurrence over 1, 2, and 5 years, evaluated through Receiver Operating Characteristic (ROC) analysis.

RESULTS
Key predictors for brain metastasis included younger age, high estrogen and progesterone receptor percentage, higher tumor size; use of aromatase inhibitor therapy, and use of selective estrogen receptor modulator therapy were associated with a decreased risk of brain metastasis. Higher grade, Ki-67 levels, HER2-positive status, lymphovascular invasion and the use of chemotherapy was associated with an increased risk. The AUC values for the prediction of brain metastasis at various time intervals in the test cohort were 0.81 at 4 years, 0.80 at 5 years, and 0.77 at 10 years. In the validation cohort, the AUCs were 0.81 at 4 and 5 years, decreasing to 0.70 at the 10-year mark.

CONCLUSIONS
This tool offers valuable support to clinicians in personalized patient care decisions regarding brain metastasis risk. Continuous validation and research will enhance these models, bolstering reliability and applicability in clinical and research settings.
BMRK-05 ASSOCIATION BETWEEN HER2-LOW STATUS AND TIME TO DEVELOPMENT OF BRAIN METASTASES AMONG PATIENTS WITH BREAST CANCER: A RETROSPECTIVE COHORT STUDY
Authors: Yijun Fan Kevin , Chehade Rania , Fernandes Italo , Moravan Veronika , Jerzak Katarzyna 
Published: August 2024

Abstract

BACKGROUND
Brain metastases (BrM) develop in a high proportion of patients with breast cancer. We aimed to investigate the association between HER2 status (HER2-0, HER2-low, HER2+) and time to BrM development in patients treated for breast cancer BrM.

METHODS
We investigated a cohort of 188 women with metastatic breast cancer (MBC) treated for BrM at Sunnybrook Odette Cancer Centre from 2008-2018, for whom HER2 status was available in either the primary breast cancer (PBC) or metastatic site. We investigated: (1) association between HER2 status of the PBC (when available) and time from PBC to BrM diagnosis (PBC-TTBM), and (2) association between HER2 status of either PBC or metastatic site (the higher level of HER2 expression was utilized when &gt;1 sample was available) and time from MBC to BrM diagnosis (MBC-TTBM).

RESULTS
Median age was 50 years and 54% of patients had &gt;1 BrM. 40 patients had triple-negative breast cancer (TNBC), 77 had HER2+ disease, and 70 had HR+(hormone receptor+)/HER2- disease. Among 129 patients for whom PBC HER2 status was available, median PBC-TTBM was 44 months. HER2-low (n=29) status was associated with shorter PBC-TTBM compared to HER2-0 (n=60) and HER2+ (n=40) status (33 vs. 50 vs. 52 months, p=0.045). Among patients with HR+/HER2- disease, HER2-low status (n=21) was associated with shorter PBC-TTBM compared to HER2-0 status (n=29) (34 vs. 95 months, p&lt;0.001). Among patients with TNBC, PBC-TTBM was similar among patients with HER2-low (n=8) and HER2-0 (n=31) status (24 vs. 27 months, p=0.79). In all patients, median MBC-TTBM was 21 months. MBC-TTBM was similar among patients with HER2-0 (n=58), HER2-low (n=53) and HER2+ (n=77) disease (15 vs.19 vs. 22 months, p=0.75); no differences were observed within the HR+/HER2- and TNBC subgroups.

CONCLUSIONS
HER2-low status is associated with shorter PBC-TTBM, particularly among patients with HR+/HER2- disease.