bluuebunny/crossref_metadata_2025 huggingface dataset:
Relativistic viscous accretion flow model for ULX sources: a case study for IC 342 X-1
Authors: Das Santabrata , Nandi Anuj , Agrawal Vivek K , Dihingia Indu Kalpa , Majumder Seshadri
Published: August 2021

In this paper, we develop a model formalism to study the structure of a relativistic, viscous, optically thin, advective accretion flow around a rotating black hole in presence of radiative coolings. We use this model to examine the physical parameters of the ultra-luminous X-ray sources (ULXs), namely mass (MBH), spin (ak), and accretion rate (${\dot{m}}$), respectively. While doing this, we adopt a recently developed effective potential to mimic the space–time geometry around the rotating black holes. We solve the governing equations to obtain the shock-induced global accretion solutions in terms of ${\dot{m}}$ and viscosity parameter (α). Using shock properties, we compute the quasi-periodic oscillation (QPO) frequency (νQPO) of the post-shock matter (equivalently post-shock corona, hereafter PSC) pragmatically, when the shock front exhibits quasi-periodic variations. We also calculate the luminosity of the entire disc for these shock solutions. Employing our results, we find that the present formalism is potentially promising to account the observed νQPO and bolometric luminosity of a well-studied ULX source IC 342 X-1. Our findings further imply that the central source of IC 342 X-1 seems to be rapidly rotating and accretes matter at super-Eddington accretion rate provided IC 342 X-1 harbours a massive stellar mass black hole ($M_{\rm BH} \lt 100 \, \mathrm{M}_\odot$) as indicated by the previous studies.
CosmoReionMC: a package for estimating cosmological and astrophysical parameters using CMB, Lyman-α absorption, and global 21 cm data
Authors: Chatterjee Atrideb , Choudhury Tirthankar Roy , Mitra Sourav
Published: August 2021

We present a Markov Chain Monte Carlo (MCMC)-based parameter estimation package, CosmoReionMC, to jointly constrain cosmological parameters of the Lambda cold dark matter (ΛCDM) model and the astrophysical parameters related to hydrogen reionization. The package is based on a previously developed physically motivated semi-analytical model for reionization, a similar semi-analytical model for computing the global 21 cm signal during the cosmic dawn and using an appropriately modified version of the publicly available camb for computing the CMB anisotropies. These calculations are then coupled to an MCMC ensemble sampler emcee to compute the posterior distributions of the model parameter. The model has 12 free parameters in total: five cosmological and seven related to the stellar populations. We constrain the parameters by matching the theoretical predictions with CMB data from Planck, observations related to the quasar absorption spectra, and, for the first time, the global 21 cm signal from EDGES. We find that incorporating the quasar spectra data in the analysis tightens the bounds on the electron scattering optical depth τ and consequently the normalization As of the primordial matter power spectrum (or equivalently σ8). Furthermore, when we include the EDGES data in the analysis, we find that an early population of metal-free stars with efficient radio emission is necessary to match the absorption amplitude. The CosmoReionMC package should have interesting future applications, e.g. probing non-standard extensions to the ΛCDM model.
BSCI-07. Multiomics characterization of brain metastases in multiple histologies identifies enrichment of oxidative phosphorylation as a promising therapeutic target
Authors: Fukumura Kazutaka , Malgulwar Prit Benny , Fischer Grant , Hu Xiaoding , Zhang Xiang , Yu Dihua , Debeb Bisrat , Davies Michael , Huse Jason
Published: August 2021

Purpose

Brain metastasis (BM) is a lethal complication from systematic malignant tumors, and the incidence is approximately 10–30% of patients with advanced cancer. Extensive genomic analyses with large sample sets and the following functional studies revealed clinically relevant characteristics for BMs. However, these studies have not identified specific abnormalities driving BM in multiple tumor histologies yet. To identify molecular pathogenesis and promising therapeutic targets shared across multiple histologies of BMs, we performed multiomics molecular profiling, along with functional studies using in vitro and in vivo BM models.

Methods

Frozen tissues of patient-matched BMs and primary tumors (or extracranial metastases) from breast cancer (N= 14), lung cancer (N = 14) and renal cell carcinomas (N = 7) patients were carried out whole-exome sequencing, mRNA-Seq and reverse-phase protein array. Paired parental and brain metastatic derivatives of MDA-MB-231 and BT474 were examined to assess findings from the multiomics datasets. SCID/beige mice were inoculated with MDA-IBC3 cells via tail vein injection and administered an oxidative phosphorylation (OXPHOS) inhibitor by oral gavage daily for 96 days.

Results

The multiomics molecular profiling identified enrichment of OXPHOS shared across the histologies of BMs. Brain metastatic derivative cell lines also demonstrated enhanced oxidative metabolism, along with the sensitivity to an OXPHOS inhibitor. Moreover, in vivo studies revealed that OXPHOS inhibition significantly impaired the formation of BM, and fresh brain metastatic derivatives from the murine BM model exhibited the higher oxidative metabolism and sensitivity to the OXPHOS inhibitor as with the prior in vitro studies.

Conclusions

Our multiomics characterization of BMs demonstrates heightened oxidative metabolism shared across the multiple histologies, and the OXPHOS inhibition affects more effectively for brain metastatic derivatives rather than the parentals. Further investigation focusing on metabolic abnormalities in BM will likely develop promising therapeutic strategies against BMs.
TRLS-03. Intracranial activity of tepotinib in patients with MET exon 14 (METex14) skipping NSCLC enrolled in VISION
Authors: Bestvina Christine M , Le Xiuning , Veillon Remi , Anderson Ian , Patel Jyoti , Demedts Ingel , Garassino Marina , Mazières Julien , Morise Masahiro , Smit Egbert , Eggleton S Peter , O’Brate Aurora , Otto Gordon , Bruns Rolf , Schumacher Karl Maria , Paik Paul
Published: August 2021

Background

Brain metastases (BMs) are reported in 20–40% patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, has demonstrated an objective response rate (ORR) of 45% and median duration of response (mDOR) of 11.1 months, in METex14 skipping NSCLC patients in Cohort A of the Phase II VISION study. Here, we report the intracranial activity of tepotinib in Cohort A.

Methods

Patients received oral tepotinib 500 mg QD. Study eligibility allowed for patients with BM (asymptomatic and symptomatic/stable). Primary endpoint: systemic objective response (RECIST v1.1); subgroup analysis in patients with BM (RECIST v1.1) was predefined.

An ad hoc retrospective analysis of brain lesions (by CT/MRI) was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For non-measurable lesions (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020.

Results

Twenty-three patients had baseline BM. Systemic efficacy in patients with BM (ORR 47.8% [95% CI: 26.8, 69.4]; mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population.

Fifteen patients were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and progressive disease (PD; n=3).

Of seven patients with measurable CNS disease (all of whom received prior radiotherapy), intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL.

Conclusions

Tepotinib demonstrated intracranial activity in patients with METex14 skipping NSCLC with BM. Prospective evaluation of intracranial activity in VISION Cohort C is ongoing.
LMD-02. Cerebrospinal Fluid Diversion for Metastatic Leptomeningeal Carcinomatosis: Palliative, Procedural and Oncologic Outcomes
Authors: Bander Evan D , Yuan Melissa , Reiner Anne S , Garton Andrew , Panageas Katherine S , Brennan Cameron W , Tabar Viviane , Moss Nelson S
Published: August 2021

Background

Leptomeningeal disease (LMD) occurs in 3–5% of patients with solid metastatic tumors and often portends a severe prognosis including symptomatic hydrocephalus and intracranial hypertension. Cerebrospinal fluid (CSF) shunting can provide symptomatic relief in this patient subset; however, few studies have examined the role of shunting in the palliation, prognosis and overall oncologic care of these patients.

Objective

To identify and evaluate risk factors associated with prognosis after CSF diversion and assess surgical, symptomatic and oncologic outcomes in this population.

Methods

A retrospective study was conducted on patients with solid-malignancy LMD treated with a shunt at an NCI-designated Comprehensive Cancer Center between 2010–2019.

Results

One hundred and ninety patients with metastatic LMD underwent CSF diversion. Overall survival was 4.14 months from LMD diagnosis (95%CI:3.29–4.70) and 2.43 months (95%CI:2.01–3.09) from shunting. KPS at time of shunting and BrM number at LMD diagnosis demonstrated significant associations with survival (HR=0.66; 95%CI[0.51–0.86], p=0.002; HR=1.40; 95%CI[1.01–1.93] per 10 BrM, p=0.04, respectively). Eighty-three percent of patients experienced symptomatic relief, and 79% were discharged home or to rehabilitation facilities post-shunting. Post-shunt, 56% of patients received additional systemic therapy or started or completed WBRT. Complications included infection (5%), symptomatic subdural hygroma/hematoma (6.3%), and shunt externalization/removal/repair (8%). Abdominal seeding was not identified.

Conclusions

CSF diversion for LMD with hydrocephalus and intracranial hypertension secondary to metastasis can achieve symptomatic relief, hospital discharge, and return to further oncologic therapy, with a complication profile unique to this pathophysiology. However, decision-making in this population must incorporate end-of-life goals of care given limited prognosis.
LMD-04. FLAIR hyperintensity along the brainstem surface in leptomeningeal metastases: a case series and literature review
Authors: Mitsuya Koichi , Nakasu Yoko , Deguchi Shoichi , Shirata Kensei , Asakura Koiku , Kazuaki Nakashima , Takahashi Toshiaki , Nakamasa Hayashi
Published: August 2021

Background

The incidence of leptomeningeal metastasis (LM) is underestimated because of its non-specific signs and the low sensitivity of clinical diagnostic modalities. Cerebrospinal magnetic resonance (MR) imaging with and without contrast enhancement (CE) is a gold standard for the neuroradiological assessment of patients with suspected LM. Previous studies suggested that some LM cases show changes of the brainstem surface on non-contrast MR images without or before the appearance of abnormalities on CE images. We assessed the features of this non-contrast MR finding in a cohort of LM patients in this retrospective single-institution study.

Methods

We reviewed head MR images and clinical data of 142 consecutive patients in whom the final diagnosis was LM.

Results

We found that 11 of these 142 patients (7.7%) with LM had band-like hyperintensity on the brainstem surface on non-enhanced FLAIR images, which looked like bloomy rind on cheese. Three of seven patients who were examined using diffusion-weighted imaging showed restricted diffusion in the corresponding lesion site. The above-mentioned 11 patients included 10 women and 1 man, with a median age of 61 years. All 11 patients had primary lung adenocarcinoma. Seven patients had symptomatic hydrocephalus. Ten patients had EGFR-mutated and one had ALK-rearrangement adenocarcinomas. Before the diagnosis of LM, 10 patients had undergone systemic therapy with EGFR-TKI or pemetrexed, and 1 patient with ALK inhibitor and bevacizumab.

Conclusions

We present a series of patients with bloomy rind sign that is non-enhancing LM reliably detected by FLAIR hyperintensity on the brainstem surface. This finding is rare, but may reflect the spread of cancer cells in both the leptomeningeal membrane and the surface of the brain parenchyma specifically in patients with lung adenocarcinomas. Further study is needed to determine the clinical significance of this sign.
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

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 < 0.032) and WM164R LMD (control: 35 days vs treatment: MS not reached; P value < 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

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

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

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 <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

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(>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

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

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 >80 (p<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<0.0001). OS was comparable in patients who received upfront SRS to less or more than 4 lesions (19.3 months for <4 [n=162] vs. 17.8 months for >/= 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

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

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

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

Obstructive 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.
Hard to Kill: Inactivation of Plasmodiophora brassicae Resting Spores Using Chemical Disinfectants
Authors: Hill T. Blake , Daniels Greg C. , Feng Jie , Harding Michael W.
Published: August 2021

Biosafety practices, such as bioexclusion via sanitization, can prevent the spread of infectious soilborne threats such as the clubroot pathogen Plasmodiophora brassicae. Twenty-three chemical disinfectants were evaluated for efficacy against P. brassicae resting spores. Evans blue staining was used to directly measure the viability of P. brassicae resting spores after 20-min exposures to 10 concentrations of each of the 23 chemical disinfectants. Only nine disinfectants were capable of >95% inactivation, and only five were capable of inactivating >99% of resting spores. Bleach (sodium hypochlorite) and Spray Nine were the most effective disinfectants for inactivation of clubroot resting spores. AES 2500, SaniDate, and ethanol also inactivated >99% of resting spores but only at very high concentrations. A time course experiment showed that 10- to 12-min contact time was sufficient for ≥95% resting spore inactivation with Spray Nine and sodium hypochlorite, but ≥30-min contact was required for other disinfectants evaluated. These results will assist in guiding management recommendations for sanitization aimed at bioexclusion and biocontainment of P. brassicae.
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

Serine 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.
Improving Leadership Competence Among Undergraduate Nursing Students: Innovative Objectives Development, Implementation, and Evaluation
Authors: Hsieh Li-Wei , Chang Yu-Chun , Yen Miaofen
Published: August 2021

AIM

The aim of the study was to identify baccalaureate nursing leadership objectives and evaluate their effectiveness when embedded into an undergraduate nursing curriculum.

BACKGROUND

The objectives of nursing leadership competencies cannot be met in one semester but must be gradually developed over successive courses.

METHOD

A list of learning objectives for leadership competence was generated and reviewed by 12 experts using the Delphi method. The consensuses objectives were embedded into a four-year nursing baccalaureate curriculum in Taiwan. Nursing students (N = 120) who participated in the courses evaluated the embedded objectives of leadership competency introduced in their undergraduate nursing program. Leadership competence was improved among students on nine items (t = 2.282 to 5.741, p = .001 to .030) of the Nursing Leadership Competence Assessment Scale for Undergraduate Nursing Students.

CONCLUSION

The results can serve as a reference for universities seeking to promote nursing leadership education.
Applying Kurtosis as an Indirect Metric of Noise Temporal Structure in the Assessment of Hearing Loss Associated With Occupational Complex Noise Exposure
Authors: Zhang Meibian , Qiu Wei , Xie Hongwei , Xu Xiaohui , Shi Zhihao , Gao Xiangjing , Zhou Lifang , Zou Hua , Hu Weijiang , Sun Xin
Published: August 2021

Objective:

The association of occupational noise-induced hearing loss (NIHL) with noise energy was well documented, but the relationship between occupational noise and noise temporal structure is rarely reported. The objective of this study was to investigate the principal characteristics of the relationship between occupational NIHL and the temporal structure of noise.

Methods:

Audiometric and shift-long noise exposure data were collected from 3102 Chinese manufacturing workers from six typical industries through a cross-sectional survey. In data analysis, A-weighted 8-h equivalent SPL (L
Aeq.8h), peak SPL, and cumulative noise exposure (CNE) were used as noise energy indicators, while kurtosis (β) was used as the indicator of noise temporal structure. Two NIHL were defined: (1) high-frequency noise-induced hearing loss (HFNIHL) and (2) noise-induced permanent threshold shift at test frequencies of 3, 4, and 6 kHz (noise-induced permanent threshold shift [NIPTS346]). The noise characteristics of different types of work and the relationship between these characteristics and the prevalence of NIHL were analyzed.

Results:

The noise waveform shape, with a specific noise kurtosis, was unique to each type of work. Approximately 27.92% of manufacturing workers suffered from HFNIHL, with a mean NIPTS346 of 24.16 ± 14.13 dB HL. The Spearman correlation analysis showed that the kurtosis value was significantly correlated with the difference of peak SPL minus its L
Aeq.8h across different types of work (p < 0.01). For a kurtosis-adjusted CNE, the linear regression equation between HFNIHL% and CNE for complex noise almost overlapped with Gaussian noise. Binary logistic regression analysis showed that L
Aeq.8h, kurtosis, and exposure duration were the key factors influencing HFNIHL% (p < 0.01). The notching extent in NIPTS at 4 kHz became deeper with the increase in L
Aeq.8h and kurtosis. HFNIHL% increased most rapidly during the first 10 years of exposure. HFNIHL% with β ≥ 10 was significantly higher than that with β < 10 (p < 0.05), and it increased with increasing kurtosis across different CNE or L
Aeq.8h levels. When L
Aeq.8h was 80 to 85 dB(A), the HFNIHL% at β ≥ 100 was significantly higher than that at 10 ≤ β < 100 or β < 10 (p < 0.05 and p < 0.01, respectively).

Conclusions:

In the evaluation of hearing loss caused by complex noise, not only noise energy but also the temporal structure of noise must be considered. Kurtosis of noise is an indirect metric that is sensitive to the presence of impulsive components in complex noise exposure, and thus, it could be useful for quantifying the risk for NIHL. It is necessary to re-evaluate the safety of permissible exposure limit of 85 dB(A) as noise with a high kurtosis value can aggravate or accelerate early NIHL.
Large Lumbar Lordosis Is a Risk Factor for Lumbar Spondylolysis in Patients with Adolescent Idiopathic Scoliosis
Authors: Sunami Takahiro , Kotani Toshiaki , Aoki Yasuchika , Sakuma Tsuyoshi , Nakayama Keita , Iijima Yasushi , Akazawa Tsutomu , Minami Shohei , Ohtori Seiji , Yamazaki Masashi
Published: August 2021

Study Design.

A retrospective, single-center, observational study.

Objective.

The aim of this study was to determine the prevalence and the characteristics of adolescent idiopathic scoliosis (AIS) patients with concomitant lumbar spondylolysis.

Summary of Background Data.

The prevalence and features of lumbar spondylolysis in patients with AIS are unclear.

Methods.

We included 357 patients with AIS who underwent correction and fusion surgery. Preoperative computed tomography (CT) images were used to assess the existence of lumbar spondylolysis. Cobb angles of the curves, parameters of spinal alignment, Lenke classification, and the presence of low back pain were compared between patients with and without spondylolysis.

Results.

Of the patients included in the study, 6.1% had lumbar spondylolysis. They had significantly greater lumbar lordosis (LL) and sacral slope (SS) than those without lumbar spondylolysis. Logistic regression analyses and receiver-operating characteristic curves showed that LL was a significant risk factor (odds ratio: 1.059; 95% confidence interval: 1.018–1.103; P = 0.005) of associating lumbar spondylolysis with a cut off value of 56.5 degrees (area under the curve [AUC]: 0.689; sensitivity = 63.6%, specificity = 71.0%).

Conclusion.

We should be vigilant for lumbar spondylolysis in AIS patients whose LL and SS are large, especially with LL larger than 56.5°.

Level of Evidence: 3
CMV and HSV Pneumonia After Immunosuppressive Agents for Treatment of Cytokine Release Syndrome Due to Chimeric Antigen Receptor–modified T (CAR-T)-Cell Immunotherapy
Authors: Heldman Madeleine R. , Ma Jimmy , Gauthier Jordan , O’Hara Riley A. , Cowan Andrew J. , Yoke Leah M. , So Lisa , Gulleen Elizabeth , Duke Elizabeth R. , Liu Catherine , Turtle Cameron J. , Hill Joshua A.
Published: August 2021

Pneumonia due to cytomegalovirus and herpes simplex virus-1 caused substantial morbidity after hematopoietic cell transplantation before the institution of preventative approaches. End-organ disease from herpesviruses is poorly described after chimeric antigen receptor–modified T-cell immunotherapy. We report 2 cases of cytomegalovirus pneumonia and 1 case of herpes simplex virus-1 gingivostomatitis, esophagitis, and pneumonia after chimeric antigen receptor–modified T-cell immunotherapy for the treatment of hematologic malignancies.
Ambient particulate matter, ozone, and neurologic symptoms in U.S. Gulf states adults
Authors: Werder Emily J. , Engel Lawrence S. , Lawrence Kaitlyn G. , Sandler Dale P.
Published: August 2021

Research on neurologic effects of air pollution has focused on neurodevelopment or later-life neurodegeneration; other effects throughout adulthood have received less attention. We examined air pollution levels and neurologic symptoms among 21,467 adults in US Gulf Coast states. We assigned exposure using Environmental Protection Agency estimates of daily ambient particulate matter 2.5 (PM2.5) and ozone. Gulf Long-term Follow-up Study participants reported neurologic symptoms at enrollment (2011–2013). We estimated cross-sectional associations between each air pollutant and prevalence of “any” neurologic, central nervous system (CNS), or peripheral nervous system (PNS) symptoms. Ambient PM2.5 was consistently associated with prevalence of neurologic symptoms. The highest quartile of 30-day PM2.5 was associated with any neurologic symptom (prevalence ratio [PR] = 1.16; 95% confidence interval [CI] = 1.09, 1.23) and there were increasing monotonic relationships between 30-day PM2.5 and each symptom category (P-trend ≤ 0.01). Associations with PM2.5 were slightly stronger among nonsmokers and during colder seasons. The highest quartile of 7-day ozone was associated with increased prevalence of PNS symptoms (PR = 1.09; 95% CI = 1.00, 1.19; P-trend = 0.03), but not with other outcomes. Ozone concentrations above regulatory levels were suggestively associated with neurologic symptoms (PR = 1.06; 95% CI = 0.99, 1.14). Mutual adjustment in co-pollutant models suggests that PM2.5 is more relevant than ozone in relation to prevalence of neurologic symptoms.
Assessing the impact of exposome on the course of chronic obstructive pulmonary disease and cystc fibrosis
Authors: Benjdir Manon , Audureau Étienne , Beresniak Ariel , Coll Patrice , Epaud Ralph , Fiedler Kristina , Jacquemin Bénédicte , Niddam Laurent , Pandis Spyros N. , Pohlmann Gerhard , Sandanger Torkjel M. , Simmons Kai , Sørensen Mette , Wagner Patrick , Lanone Sophie
Published: August 2021

Because of the direct interaction of lungs with the environment, respiratory diseases are among the leading causes of environment-related deaths in the world. Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest in the context of environmental studies; they both are characterized by a similar progressive loss of lung function with small bronchi alterations, and a high phenotypic variability of unknown origin, which prevents a good therapeutic efficacy. In the last years, there has been an evolution in the apprehension of the study of diseases going from a restricted “one exposure, one disease” approach to a broader concept with other associating factors, the exposome. The overall objective of the REMEDIA project is to extend the understanding of the contribution of the exposome to COPD and CF diseases. To achieve our aim, we will (1) exploit data from existing cohorts and population registries to create a unified global database gathering phenotype and exposome information; (2) develop a flexible individual sensor device combining environmental and biomarker toolkits; (3) use a versatile atmospheric simulation chamber to simulate the health effects of complex exposomes; (4) use machine learning supervised analyses and causal inference models to identify relevant risk factors; and (5) develop econometric and cost-effectiveness models to assess the costs, performance, and cost-effectiveness of a selection of prevention strategies. The results will be used to develop guidelines to better predict disease risks and constitute the elements of the REMEDIA toolbox. The multidisciplinary approach carried out by the REMEDIA European project should represent a major breakthrough in reducing the morbidity and mortality associated with COPD and CF diseases.