bluuebunny/crossref_metadata_2025_split huggingface dataset:
LMD-07. In Vitro AND In Vivo Culture of Patient Derived-Cerebral Spinal Fluid-Circulating Tumor Cells (PD-CSF-CTCs) in Leptomeningeal Disease (LMD) From Melanoma to Identify Novel Treatment Strategies
Authors: Law Vincent , Chen Zhihua , Smalley Inna , Vena Francesca , Macaulay Robert , Evernden Brittany , Tran Nam , Chen Ann , Pina Yolanda , Caceres Gisela , Puskas John , Duckett Derek , Smalley Keiran , Forsyth Peter 
Published: August 2021

Abstract

Background
Approximately 5% of melanoma patients (pts) will develop LMD. Currently there is no effective treatments for this disease. A significant barrier to the development of effective therapies has been the inability to culture CSF-CTCs for functional analysis. For the first time, we were able to successfully expand CSF-CTCs in vitro and in vivo. We assessed gene signatures of PD-CSF-CTCs to determine novel targets for therapy. As a proof of concept, we tested the efficacy of combining ceritinib (cer), an IGF-1R inhibitor and trametinib (tra), a MEK inhibitor, against LMD.

Methods
CSF from 11 pts were collected from various sources (ie: LPs, Ommayas, rapid autopsies). PD-CSF-CTCs were expanded in vitro in conditioned media and in vivo using cell line-derived xenograft model. Single-cell RNA-sequencing (scRNAseq) analysis was performed to assess transcriptional profiles of PD-CSF-CTCs.

Results
Of the total 61 PD-CSF-CTCs collected from 11 pts (avg: 4.07 CSF collections/patient), we successfully cultured PD-CSF-CTCs from 3 pts (20%) and were able to grow them in vivo from 2 pts (18%). scRNAseq identified IGF-1R, Sox9, ErbB3 and MLANA were among the enriched genes for PD-CSF-CTCs. IGF-1R inhibition by cer and depletion by CRISPR suppressed cell growth. We evaluated the responses of cer + tra treatment in vitro and found that combining these agents produced drug synergy against PD-CSF-CTCs and resensitized BRAF inhibitor-resistant melanoma cell line, WM164R. In vivo LMD xenograft model showed cer + tra treatment significantly prolonged median survival of PD-CSF-CTCs LMD (control: 27 days vs treatment: 38.5 days; P value &lt; 0.032) and WM164R LMD (control: 35 days vs treatment: MS not reached; P value &lt; 0.047).

Conclusions
Though the sample size is small, this is the first report of the successful in vitro and in vivo culture of CSF-CTCs from pts with LMD.
LMD-13. ReSPECT-LM: Maximum tolerated dose, safety, and efficacy of intraventricular Rhenium-186 Nanoliposome (186RNL) for leptomeningeal metastases
Authors: Brenner Andrew , Floyd John , Bao Ande , Phillips William , Stein Gregory 
Published: August 2021

Abstract

Introduction
Leptomeningeal metastases (LM) are a rare but typically fatal complication of advanced cancer that affects the fluid-lined structures of the central nervous system and are diagnosed in approximately 5 percent of patients with metastatic cancer. With survival measured in weeks to months, novel approaches are needed that can both improve quality and quantity of life. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation of high specific activity directly to the tumor. In a Phase 1 trial in adults with recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor when coverage was 75% or greater (n=10) was 392 Gy (CI 306 – 478). Thus far, the therapy has been well tolerated with one possible treatment-related serious adverse event, cerebral edema, that resolved after steroid treatment.

Methods
This is a two-part, Phase 1 dose-finding study followed by an expansion cohort to explore efficacy. Part 1 will enroll up to 21 subjects to characterize the safety and tolerability of a single dose of 186RNL administered intraventricularly via an Ommaya reservoir and to identify a maximum tolerated dose (MTD) / maximum feasible dose (MFD) for future studies. The dose limiting toxicity period is 28 days post infusion. Part 2 will independently evaluate 186RNL in 2 different cohorts: Cohort A: up to 20 subjects with a diagnosis of LM from primary breast cancer; Cohort B: up to 20 subjects with a diagnosis of LM from primary non-small cell lung cancer. The primary endpoint is to estimate the anti-tumor activity of 186RNL as a single agent. Secondary endpoints are to characterize the pharmacokinetic and dosimetry profile of a single dose of 186RNL, determine the overall response rate (ORR) based on CSF and radiographic findings, and to describe the survival distribution. Planned enrollment will begin in H2 2021.
LMD-16. Choroid plexus orchestrates anti-cancer immunity in leptomeninges
Authors: Remsik Jan , Tong Xinran , Li Min Jun , Sener Ugur , Wilcox Jessica , Chabot Kiana , Kunes Russell , Isakov Danielle , Osman Ahmed , Yang T Jonathan , Bale Tejus , Pe’er Dana , Boire Adrienne 
Published: August 2021

Abstract
Choroid plexus (CP) forms an anatomically functional barrier between the blood and cerebrospinal fluid (CSF) that dictates the cellular and humoral composition of the CSF. The immunological response of CP to inflammatory stimuli, such as cancer, remains unclear. Here, we find that CP orchestrates the immune composition of CSF in the steady state as well as in the presence of metastatic cancer. We show that the circulation-derived leptomeningeal monocyte-macrophages entering the CSF through CP promote the growth of leptomeningeal metastasis (LM) by perturbing the environment with a storm of dozens of pro- and anti-inflammatory cytokines. Functional manipulation of Type II Interferon pathway specifically within inflamed leptomeninges revealed that IFN-γ can serve as a dominant signal, further recruiting peripheral myeloid cells and activating their protective anti-tumoral response. This preclinical strategy was sufficient to controll the growth of syngeneic LM cancer cells and delay the onset of lethal LM.
LMD-18. Detection and serial monitoring of CSF ctDNA in breast cancer leptomeningeal disease (BCLM)
Authors: Fitzpatrick Amanda , Iravani Marjan , Okines Alicia , Mills Adam , Harries Mark , Tutt Andrew , Isacke Clare 
Published: August 2021

Abstract

Background
CSF cytology is the gold standard diagnostic test for BCLM, but is hampered by a low sensitivity, often necessitating repeated lumbar puncture to confirm or refute the diagnosis. Furthermore, during the treatment of BCLM, there is no robust quantitative response tool to guide treatment decisions.

Material and Methods
cfDNA was obtained from CSF and plasma in patients with breast cancer undergoing investigation for BCLM (n = 28) and during subsequent intrathecal treatment (n = 13). Ultra low pass whole genome sequencing (ulpWGS) and estimation of the ctDNA fraction was performed. Results were validated by mutation-specific digital droplet PCR (ddPCR).

Results
22/28 cases had confirmed BCLM by positive MRI and/or CSF cytology. The remaining 6/28 had suspected but non-confirmed BCLM, and at median 20 months follow up, these patients were BCLM-free.
CSF ctDNA fraction was significantly elevated (median 57.5, IQR 38.3 - 84.9%) in confirmed BCLM compared to 6 non-confirmed BCLM (median 5.0, IQR 0.0 - 6.7%) (p &lt;0.0001). ctDNA fraction was detected in BCLM confirmed cases regardless of negative cytology or MRI. Plasma ctDNA fraction was only detected in extra-cranial disease progression. ctDNA fraction was concordant with mutant allele fraction measured by ddPCR (n = 118 samples).
Serial CSF ctDNA fraction during intrathecal treatment showed dynamic changes, while CSF cytology and MRI were often unchanged or equivocal. Early reduction in CSF ctDNA fraction was associated with longer responses to intrathecal therapy. Further, rising ctDNA fraction during intrathecal chemotherapy could be detected up to 6 weeks before relapse in neurological symptoms, cytology or MRI.

Conclusion
Measuring CSF ctDNA fraction is a sensitive diagnostic test for BCLM and could lead to more timely and accurate diagnosis. During intrathecal chemotherapy, CSF ctDNA also provides a quantitative response biomarker to help guide clinical management in this difficult treatment scenario.
MLTI-01. Study on the Association between Prone Locations and Prognosis of Breast Cancer Brain Metastases via Voxel Analysis
Authors: Wang Hairong , Duan Hao , Chen Hongyu , Jiang Dongping , Mou Yonggao , Yao Maojin , Guo Chengcheng 
Published: August 2021

Abstract

Purpose
This study aimed to analyze the preferred locations of secondary brain tumors of breast carcinoma according to different biological characteristics.

Method
161 Breast cancer brain metastasis (BCBM) patients diagnosed between January 2007 and February 2018 were retrospectively analyzed. MR images when brain metastases occurred were collected, registered, segmented. The frequency and p-value heatmaps were constructed to compare two biological phenotypes using two-tailed Fisher’s exact test. Age, treatments, the status of ER, PR, and HER2, luminal subtype, tumor marker levels in peripheral blood including CEA, CA19-9, and CA15-3 were statistically analyzed. Survival data were analyzed by Kaplan–Meier method, log-rank test, and multivariate logistic regression.

Result
The frequency heat map shows lesions of patients with BCBM are more inclined to the cerebellar hemisphere. Older patients(&gt;49 years old, median age) mainly occur in the left frontal lobe, the right parietal lobe, and adjacent meninges comparing with white matter of the left parietal lobe, cerebellar vermis, and areas around the fourth ventricle among younger patients and the difference is significant. Patients with tumors located on the surface of the brain are more likely to undergo surgical treatment, however, conservative treatment was considered if metastases are located at the midline structure. ER and PR-positive and HER-2 enriched patients have more significance in metastases, at the left parieto-occipital junction area, frontal lobe, parietal lobe, cerebellar hemisphere, and adjacent meninges. Metastases with high levels of CEA are found significantly at areas around the central anterior gyrus. Lesions with an elevated level of CA19-9 and CA15-3 tend to be frontal, parietal, and occipital. Besides, HER-2 enriched in primary sites and a normal level of CA15-3 in peripheral blood were two independent protective factors in determining prognostic outcomes.

Conclusion
The preferred locations of BCBM could be clues of further study and helpful for clinical strategies.
RADI-11. Evaluating the Tissue Effects of Dose-escalated Pre-operative Stereotactic Radiotherapy for Resectable Brain Metastasis
Authors: Kotecha Rupesh , Tonse Raees , Menendez Miguel A Ramirez , Williams Andre , Diaz Zuanel , Tom Martin C , Hall Matthew D , Mehta Minesh P , Siomin Vitaly , Ahluwalia Manmeet S , McDermott Michael W 
Published: August 2021

Abstract

Background
Although the classic radiobiologic principles of radiotherapy are well understood, the unique effects of the large fractional does that characterize stereotactic radiotherapy (SRT), specifically in terms of antitumor immune cellular processes, vascular damage, tumor necrosis, and apoptosis on brain metastasis have yet to be adequately demonstrated. The objective of this study is to provide the first in-human evaluation of the biological effects of SRT in resected brain metastasis.

Methods
All paired primary tumors and metastases for patients who underwent dose-escalated preoperative SRT followed by resection were evaluated for tumor necrosis using hematoxylin-eosin staining. T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), vessel density (CD31+), and apoptotic factors (caspase-3) were determined by immunohistochemical analysis.

Results
Fifteen patients with brain metastases from solid tumors received a median preoperative SRT dose of 18 Gy (range: 15–18 Gy) in 1 fraction, with 2 patients receiving 27–30 Gy in 3–5 fractions, followed by resection within a median interval of 90 hours (Range: 17.1–260 hours). The rate of necrosis was found to be significantly higher in irradiated brain metastases than in non-irradiated primary tumor samples (mean paired difference: 30.47, SD: 29.28, p=0.001). A decrease in all immunomodulatory cell populations was found in irradiated metastasis: CD3 (mean paired difference -19.4, SD: 31.7, p=0.03), CD4 (-10.0, SD: 20, p=0.01), and CD8 (-17.4, SD: 22.1, p=0.008). While irradiated samples had numerically lower CD 31+, CD 56+, and caspase-3 scores, the difference was not statistically significant. Time interval from SRT to surgery had no effect on these parameters.

Conclusions
There is complex interplay between tumor-associated cells and the unique radiobiological effects of SRT on tumor tissue. Although time interval from SRT to surgery was associated with increased tumor necrosis, differences in immunomodulatory factors may be multifactorial, including concurrent corticosteroids or the immunosuppressive effect of SRT.
RADI-18. Survival and disease control after upfront stereotactic radiosurgery for brain metastases from breast cancer
Authors: Wang Yan , An Ran , Wang Fuchenchu , Gao Chao , Raghavendra Akshara Singareeka , Kim Yon Son Betty , Briere Tina Marie , Amaya Diana N , Li Jing 
Published: August 2021

Abstract

Background
As systemic therapy for metastatic breast cancer (BC) improves, the survival benefit from hormonal and targeted therapy urges treatment of brain metastases (BMs) with minimal toxicity and less systemic therapy interruption. Here we assessed clinical outcomes in BC patients who received upfront stereotactic radiosurgery (SRS).

Methods
We identified 236 patients who received upfront SRS with/without surgery for BMs from metastatic BC from 06/2007 to 05/2018. Twenty-four patients who received SRS for surgical cavity were excluded for analysis. Overall survival (OS) and salvage radiation-free survival (SRFS) were estimated using Kaplan-Meier analysis. Cox proportional hazard regression was used to identify prognostic factors.

Results
At a median follow-up time of 15.4 months (range, 0.8–119.6), the estimated median OS was 18.5 mo (95% CI, 14.9–21). Factors associated with OS on multivariate analysis (MVA) were molecular subtypes (12.2 months for triple-negative [n=68], 13.3 months for HR+/HER2- [n=66], 36.4 months for HR+/HER2+ [n=46], and 28.1 months for HER2+ [n=32], p=0.002), KPS &gt;80 (p&lt;0.0001), receipt of chemotherapy (p=0.016) or anti-HER2 therapy (p=0.029) after diagnosis of BM, and type of salvage radiation (p&lt;0.0001). OS was comparable in patients who received upfront SRS to less or more than 4 lesions (19.3 months for &lt;4 [n=162] vs. 17.8 months for &gt;/= 4 [n=50], p=0.36). The 12-month salvage RT rate was 25% for WBRT and 26.4% for SRS. The median SRFS was 7.4 months (95% CI, 6.5‒8.3). Factors associated with SRFS on MVA were subtypes (p=0.002), KPS (p=0.011), and receipt of hormone therapy after diagnosis of BM (p=0.031).

Conclusions
The median OS for BC patients who developed BM is over 15 months. Molecular subtypes (HER2+ and HR+/HER2+), good KPS, and anti-HER2 or hormone therapy predicted better OS and SRFS. Prospective studies are needed to verify these results and refine the best treatment strategies for these patients.
RADI-21. Feasibility of Gamma Knife Surgery for patients with 20 or more brain metastases
Authors: Jiani Liu Sherry , Karlsson Bengt , Tan Choo Heng , Balamurugan Vellayappan , Ang Yvonne , Nga Vincent , Yeo Tseng Tsai 
Published: August 2021

Abstract

Background
The current standard-of-care treatment for brain metastases (BM)≥20 is Whole Brain Radiotherapy (WBRT), which can cause neurocognitive decline detrimental to patients’ quality of life, especially if their functional status is good on presentation. The benefits of Gamma Knife Surgery (GKS) have been shown for BM≤10, but there is no consensus on the upper limit where GKS is no longer beneficial. We hypothesize that selected patients with ≥20 BM may benefit by replacing WBRT with GKS to preserve neurocognition without compromising intracerebral tumor control and overall survival, with additional treatments as needed.

Methodology
This is retrospective analysis of 31 patients with ≥20 BM who underwent single-session GKS between 2016–2021. Twenty-two patients had ECOG of 0 at the time of GKS. Median number of BM at GKS was 30 (20–79) with median total tumour volume 4cm3 (2–28 cm3). Median marginal dose was 20Gy (10-25Gy).

Results
Median overall survival following GKS was 14-months (95%CI 4-24months), justifying GKS in this population. 11/12 patients that died succumbed due to extracranial disease, while 1 patient, who was treated with WBRT before GKS, succumbed to intracranial tumor progression. Local tumor control achieved was achieved for 63% of patients at 2-years and distal tumor control in 24% of patients at 1.5-years without additional radiation treatment. Salvage GKS was given in seven patients and salvage WBRT in three. One local recurrence was surgically resected. Systemic treatment given to most patients probably contributed to intracranial tumor control. No patients developed significant neurocognitive deficits attributable to GKS during the follow-up period of median 7-months (Q1-Q3: 3-12months).

Conclusion
Most patients treated with GKS for ≥20 BM have sufficient survival time to benefit from the treatment. Local and distal recurrences can be managed with systemic treatment, salvage GKS, or WBRT, resulting in intracerebral tumor control in vast majority of cases.
Private and public consumption: substitutes or complements?
Authors: Jalles João Tovar , Karras Georgios 
Published: August 2021

Abstract
This article investigates the degree to which government consumption expenditures substitute or complement private consumption, one of the most important (and most overlooked) determinants of the fiscal multiplier. Using panel datasets from a large number of heterogeneous economies over 1970–2016, we find that private and government consumption are best described as complementary both in the aggregate and for nine different categories of government spending we consider. The degree of complementarity, however, differs substantially across government spending categories, being the highest for education, recreation, and housing in the Organisation for Economic Co-Operation and Development (OECD); and for Public Order and Recreation in the non-OECD. Our estimates imply that fiscal multiplier values in those spending categories are substantially higher than in categories that are less (or not at all) complementary with private consumption.
Nonpharmaceutical Interventions Remain Essential to Reducing Coronavirus Disease 2019 Burden Even in a Well-Vaccinated Society: A Modeling Study
Authors: León Tomás M , Vargo Jason , Pan Erica S , Jain Seema , Shete Priya B 
Published: August 2021

Abstract
Vaccination and nonpharmaceutical interventions (NPIs) reduce transmission of severe acute respiratory syndrome coronavirus 2 infection, but their effectiveness depends on coverage and adherence levels. We used scenario modeling to evaluate their effects on cases and deaths averted and herd immunity. NPIs and vaccines worked synergistically in different parts of the pandemic to reduce disease burden.
Obstructive Sleep Apnea Is Treatable With Continuous Positive Airway Pressure in People With Schizophrenia and Other Psychotic Disorders
Authors: Giles Jamilla J , Ling Ivan , McArdle Nigel , Bucks Romola S , Cadby Gemma , Singh Bhajan , Morgan Vera A , Gabriel Laura , Waters Flavie 
Published: August 2021

AbstractObstructive sleep apnea (OSA) is a highly prevalent condition in people living with schizophrenia or other psychotic disorder. Its treatment with continuous positive airway pressure therapy (CPAP) can dramatically improve daytime and physical health function. People with a psychotic disorder, however, are rarely diagnosed and treated and there are no large-scale studies showing evidence of successful treatment with CPAP. Using a retrospective case-control study approach (N = 554), we examined adherence to and effectiveness of a CPAP trial in individuals with comorbid psychotic disorder and OSA (psychosis group, n = 165) referred for a CPAP trial at the West Australian Sleep Disorders Research Institute. Given that antipsychotic medication is an important confounder, we included a psychiatric (non-psychosis) comparison group taking antipsychotic medication (antipsychotic group, n = 82), as well as a nonpsychiatric control group (OSA control group, n = 307) also diagnosed with OSA and referred for CPAP. Variables included OSA symptom response, CPAP engagement, and usage at 3 months. The Psychosis group had the most severe OSA at baseline and they attended fewer clinic appointments overall. However, there were no other group differences either in CPAP adherence or treatment response. CPAP was equally effective in normalizing OSA symptoms and daytime sleepiness in all groups. CPAP usage was longer per night in the Psychosis and Antipsychotic groups, perhaps suggesting a role of sedation from antipsychotic medications. In conclusion, OSA is treatable and CPAP feasible in people with severe mental illness and antipsychotic medications are not a barrier to treatment response.
Bone morphogenetic protein 2 upregulates SERPINE2 expression through noncanonical SMAD2/3 and p38 MAPK signaling pathways in human granulosa‐lutein cells
Authors: Luo Xiaoyan , Chang Hsun‐Ming , Yi Yuyin , Leung Peter C. K. , Sun Yingpu 
Published: August 2021

AbstractSerine protease inhibitor‐E2 (SERPINE2) is highly expressed in the granulosa cells of growing follicles and the dynamic changes in SERPINE2 expression are correlated with follicular development and ovulation in several mammals, including mice, cattle, sheep, and humans. Bone morphogenetic proteins (BMPs) and their functional receptors are extensively expressed in the ovary and play critical roles in the regulation of ovarian folliculogenesis and luteal function. To date, whether BMPs regulate the expression of SERPINE2 during human follicular development remains to be elucidated. The aim of this study was to investigate the effects of BMPs on the regulation of SERPINE2 expression (a major regulator of plasminogen activators [PA]) and the underlying mechanisms using primary and immortalized human granulosa‐lutein (hGL) cells. Our results demonstrated that these BMPs (BMP2, BMP4, BMP6, BMP7, and BMP15) induced differential upregulation of SERPINE2 expression. In this regard, BMP2 is the major modulator that has the best cellular activity, which further decreased the production of urokinase PA and tissue PA in hGL cells. In addition to canonical SMAD1/5/8 signaling, BMP2 also activates noncanonical SMAD2/3 and p38 mitogen‐activated protein kinase (MAPK) signaling. Using two inhibition approaches (kinase receptor inhibitors and siRNA‐mediated knockdown), we found that SMAD2/3‐SMAD4 and p38 MAPK, but not SMAD1/5/8 signaling, was involved in the BMP2‐induced upregulation of SERPINE2 expression via activin receptor‐like kinase 3. These findings deepen our understanding of the differential effect of BMPs in regulating follicular function and provide new insights of the molecular mechanisms by which BMP2 regulates the expression of SERPINE2 in human granulosa cells.