bluuebunny/crossref_metadata_2025_split huggingface dataset:
21. A PHASE II TRIAL OF COMPREHENSIVE TREATMENT BASED ON RADIOTHERAPY IN LEPTOMENINGEAL METASTASIS
Authors: Yang Siran , Liu Qingfeng , Xiao Jianping , Zhang Hongmei , Bi Nan , Zhang Ye , Ma Yuchao , Wang Kai , Chen Xuesong , Zhao Ruizhi , Wu Xi , Li Junling , Yi Junlin , Wang Shulian , Wang Yexiong 
Published: August 2020

Abstract

OBJECTIVES
To investigate the efficacy and security prospectively for patients with leptomeningeal metastases (LM) of comprehensive treatment based on radiotherapy.

METHODS
From 2014 to 2017, 93 patients diagnosed with LM admitted to our hospital who underwent whole brain radiotherapy (WBRT) or craniospinal irradiation (CSI) with or without simultaneously boost were enrolled. The dynamic changes of enhanced magnetic resonance imaging, clinical signs and symptoms, cerebrospinal fluid cytology and liquid biopsy detection were recorded. The primary endpoint was overall survival (OS), the secondary endpoints were local control (LC), intracranial progress-free survival (IPFS), brain metastasis specific survival (BMSS) and toxicity.

RESULTS
The major primary diagnosis was non-small cell lung cancer. Subjects received WBRT with boost (40 Gy in 20 fractions (f) for WBRT and 60Gy in 20 f for boost), focal radiation to LM, WBRT and CSI (40 Gy in 20 f or 50Gy in 25 f for WBRT and 36 Gy in 20 f for CSI). 20 patients were found tumor cells and were administrated intrathecal chemotherapy. 63 patients used target therapy. The median follow-up time was 33.8 months. OS/LC/IPFS at 1 year were 62.4%/77.2% and 52.6%, respectively. The median survival time was 15.9 months, and the median brain metastasis-specific survival was 42.2 months. Treatment-related grade 3–4 adverse events were rare and included eight grade 3 hematological toxicity.

CONCLUSION
Reasonable comprehensive treatment including precise radiotherapy, intrathecal chemotherapy and targeted agents were well tolerated and could extend the survival time of LM patients compared with historical controls.
24. LOCAL TUMOR PROGRESSION IS A RISK FACTOR FOR POSTOPERATIVE SEIZURES IN PATIENTS WITH BRAIN METASTASIS
Authors: Grossenbacher Bettina , Moors Selina , Lareida Anna , Roth Patrick , Imbach Lukas , Le Rhun Emilie , Weller Michael , Wolpert Fabian 
Published: August 2020

Abstract

PURPOSE
Brain tumor-related epilepsy (BTRE) occurs in 20–35% of patients with brain metastases (BM) and influences morbidity, mortality as well as quality of life. Several factors associated with seizure risk have been identified, including incomplete resection and supratentorial localization of BM. In primary brain tumors like lower grade glioma, tumor growth is associated with seizures. However, it remains to be elucidated whether this holds also true for patients with BM. METHOD: We identified 295 patients who had been diagnosed with BM between 2004 and 2014 by review of our electronic chart system. Occurrence of new onset of postoperative seizures dependent on BM progression was tested during the clinical course as well as pattern of progression and previously described predictors of postoperative seizures. Chi-square test was used for univariate analysis, a Cox-regression model for multivariate testing.

RESULTS
Postoperative seizures were observed in 49 of 295 patients (16.6%). Supratentorial localization (p=0.043, OR 4.45, 95% CI 1.1–19.3) and incomplete resection (p=0.018, OR 3.68, 95% CI 1.4–10.9), along with intracranial (p=0.038, OR 1.4, 95% CI 1.4–5.8) but not extracranial progression (p=0.729, OR 0.90, 95% CI 0.4–1.7) were confirmed as factors independently associated with postoperative seizures. Furthermore, there was a significantly higher rate of postoperatives seizures in patients with local progression (18 of 84 patients, 21.4 %) compared to those with distant brain progression (12 of 93 patients, 12.9%, p=0.042, Chi-square test).

CONCLUSION
Here we define tumor progression as a risk factor for the development of postoperative seizures in a well defined cohort of BM patients. Extracranial tumor recurrence seems to be not significant for seizure risk. Subgroup analysis indicates that patients with local progression of BM are more prone to seizures than those with new, distant BM lesions. Patients with local tumor recurrence might thus be candidates for primary prophylaxis with antiepileptic drugs.
25. EFFECT OF STEREOTACTIC RADIOSURGERY COMPARED TO WHOLE-BRAIN RADIOTHERAPY FOR LIMITED BRAIN METASTASIS ON LONG TERM COGNITION AND QUALITY OF LIFE: A POOLED ANALYSIS OF NCCTG N107C/CEC.3 AND N0574 (ALLIANCE) RANDOMIZED CLINICAL TRIALS
Authors: Palmer Joshua , Klamer Brett , Ballman Karla , Brown Paul , Cerhan Jane , Anderson Keith , Whitton Anthony , Greenspoon Jeffrey , Chung Caroline , Burri Stuart , Parney Ian , Stieber Volker , Pollock Bruce , Laack Nadia , Ashman Jonathon , Bahary Jean-Paul , Barker Fred , Galanis Evanthia , Asher Anthony , Roberge David 
Published: August 2020

Abstract

PURPOSE
We investigated the long term impact of SRS and WBRT in two large prospective phase III trials.

METHODS
Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of &gt;1 standard deviation from baseline in &gt;2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences in trend over time between groups and the effect of &gt;2 cognitive scores with &gt;2 SD change from baseline were assessed.

RESULTS
88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in &gt;1 and &gt;2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in &gt;3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in &gt;1 CM at every time point. SRS had fewer patients with a 2 SD decline at &gt;2 and &gt;3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p&lt;0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p&lt;0.001).

CONCLUSIONS
We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.
35. EVALUATING CSF CIRCULATING TUMOR DNA IN INTRAPARENCHYMAL BRAIN METASTASIS
Authors: Cheok Stephanie , Narayan Azeet , Arnal-Estape Anna , Patel Abhijit , Nguyen Don , Chiang Veronica 
Published: August 2020

Abstract

INTRODUCTION
Discordant response between brain and systemic metastases occur in patients receiving targeted therapies and repeat tumor profiling of the progressing site could guide further therapy. We propose that circulating tumor DNA (ctDNA) might be detectable in the cerebrospinal fluid (CSF) and reflective of the genetic profile of intraparenchymal brain metastases.

METHODS
Patients with brain metastases undergoing a craniotomy or lumbar puncture were enrolled between July 2018 to April 2019 under an IRB-approved protocol. CSF and blood were collected simultaneously. Cell-free DNA (cfDNA) were extracted and ctDNA were identified and quantified using an Error-Suppressed Deep Sequencing method previously published by our group. Forty-three mutation-prone regions of 24 cancer-associated genes were assayed, and the allelic fractions were calculated against wild-type sequence counts.

RESULTS
Sixteen patients were enrolled in this study - 12 patients with intraparenchymal brain metastases, two patients with CSF cytology-positive leptomeningeal disease (LMD) and 2 patients with normal pressure hydrocephalus (NPH) as controls. Primary cancer types were lung (n=10), melanoma (n=2), renal cell (n=1) and colorectal (n=1) cancers. cfDNA was found in all sixteen samples of CSF. CSF ctDNA were found in eight patients (67%) and plasma ctDNA were only found in five patients (42%) with intraparenchymal tumors. In six patients with additional time-matched brain metastasis tissue, four were found to have congruent mutations in the CSF, while only one harbored such mutation in the plasma.

DISCUSSION
Analysis of CSF can be a viable alternative to obtaining brain metastasis tissue for DNA profiling in the detection of novel and resistance mutations. The presence CSF ctDNA is not restricted to LMD and were isolated from two-thirds of patients with intraparenchymal disease in our cohort. Furthermore, CSF remains a better source than plasma for the detection of ctDNA across multiple brain metastases tumor subtypes.
36. A PROSPECTIVE TRIAL OF RESECTION PLUS SURGICALLY TARGETED RADIATION THERAPY FOR BRAIN METASTASIS
Authors: Brachman David , Nakaji Peter , Smith Kris , Youssef Emad , Thomas Theresa , Pinnaduwage Dilini , Rogers C Leland 
Published: August 2020

Abstract

INTRODUCTION
Achieving durable local control for larger brain metastases remains problematic. Resection (R) alone is typically insufficient. Even with the addition of stereotactic radiation the 12-month recurrence rate for larger lesions (i.e., &gt;2.5–3 cm) is 20% or more in many series. To improve outcomes we designed and prospectively evaluated a permanently implanted radiation device consisting of Cs-131 seeds positioned within a collagen tile (GammaTile, GT Medical Technologies, Tempe AZ). We combined maximum safe resection and collagen tile brachytherapy (CTBT) with the hypothesis that immediate radiation initiation and/or dose intensification could improve outcomes.

MATERIALS/METHODS
From 2013–2018 patients undergoing resection with either previously untreated or recurrent brain metastasis were enrolled on a single arm, multi-histology study (ClinicalTrials.gov, NCT#03088579). At resection completion the tumor bed was lined with collagen tiles imbedded with Cs-131, delivering 60–80 Gy at 5 mm depth. The device was designed to prevent direct source-to-brain contact and to maintain inter-source spacing after closure. No additional local therapy was given unless progression occurred.

RESULTS
16 metastases (12 recurrent/4 previously untreated) in 11 patients were treated. Median diameter 3.1 cm, range 1.9–5.1. Histology was 7 breast, 6 lung, and 3 sarcoma. Median age 60 years; 7 females/4 males. Average time for implantation was 5 minutes. At median radiographic follow-up of 9.5 months (range 0.1–25.2) treatment site progression occurred 1/16 (6%) at 10.9 months. Median treatment site time-to-progression (TTP) has not been reached (95% CI, &gt;10.9 months). Median overall survival (OS) 9.3 months. No surgical adverse events occurred. One patient (6.2%) experienced radiation brain changes and was treated medically.

CONCLUSION
R+CTBT demonstrated excellent safety and local control outcomes in this single-arm pre-commercial study. The device recently received FDA clearance for use in newly diagnosed and recurrent brain metastasis. Randomized clinical trials vs standard of care treatments are expected to open in 2020.
37. IN VIVO FUNCTIONAL GENOMIC SCREEN TO IDENTIFY NOVEL DRIVERS OF LUNG-TO-BRAIN METASTASIS
Authors: Aghaei Nikoo , Lam Fred , Venugopal Chitra , Singh Sheila 
Published: August 2020

Abstract
Brain metastasis, the most common tumour of the central nervous system, occurs in 20–36% of primary cancers. In particular, 40% of patients with non-small cell lung cancer (NSCLC) develop brain metastases, with a dismal survival of approximately 4–11 weeks without treatment, and 16 months with treatment. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). Genomic interrogation of LBM using CRISPR technology can inform preventative therapies targeting genetic vulnerabilities in both primary and metastatic tumours. Loss-of-function studies present limitations in metastasis research, as knocking out genes essential for survival in the primary tumour cells can thwart the metastatic cascade prematurely. However, gene overexpression using CRISPR activation (CRISPRa) has the potential for overcoming dependencies of gene essentiality. We theorize that an in vivo genome-wide CRISPRa screen will identify novel genes that, when overexpressed, drive LBM. We have developed a patient-derived orthotopic murine xenograft model of LBM using primary patient-derived NSCLC cell lines (termed LTX cells) from the Swanton Lab TRACERx study. We are now poised to transduce LTX cells with a human genome-wide CRISPRa single guide RNA (sgRNA) library, and to subsequently inject the cells into the lungs of immunocompromised mice. We will then track the process of LBM using bioluminescent and MRI imaging until mice reach endpoint. Sequencing of primary lung tumours and subsequent brain metastases promises to uncover enriched sgRNAs, which may represent novel drivers of primary lung tumour formation and LBM. To the best of our knowledge, this study is the first in vivo genome-wide CRISPRa screen focused on identifying novel drivers of LBM, and can inform future preventative therapies to improve survival outcomes for NSCLC patients.
40. AN UPDATE ON THE DEVELOPMENT OF A NEW TOOL TO ASSESS RESPONSE IN LEPTOMENINGEAL METASTASIS
Authors: Weller Michael , Le Rhun Emilie 
Published: August 2020

Abstract
In 2016, a standardized scorecard to aid in the evaluation of MRI findings during the course of disease was proposed by the RANO leptomeningeal metastasis (LM) subcommittee. In this scorecard, LM main features and the different CNS metastases types were to be reported as present or absent, dimensions of measurable nodules were to be noted, and changes from the previous MRI were to be scored from -3 to +3. A feasibility and validation study of this scorecard was performed by asking 19 experts to evaluate response in 22 patients diagnosed with and treated for LM. The outcome was disappointing in that the scorecard appeared to be too complicated (Le Rhun et al. Neuro-Oncology 2019;21:648–658). Specific challenges were (i) to understand that the form should be used to rate the current MRI and to compare it with the previous one, (ii) to use the proposed rating with “minus” or “plus” options to assess the change and (iii) to derive a sum score that does not take into consideration (per instruction) changes for the items “hydrocephalus”, “brain metastases” and “parenchymal medullary metastases”. In addition to the apparent challenges for experienced raters to use the LANO scorecard instructions without further instructions, we identified additional weaknesses. These include to eliminate epidural metastases from response assessment, to include the definition of a nodule, the distinction of leptomeningeal versus parenchymal brain disease, and to include parallel, but clearly separate criteria to document brain parenchymal disease. The revised, published proposal for a new scorecard has been used to rate another series of LM cases by experienced neuro-oncologists from March to May 2020. First analyses of this novel feasibility and validation study will be available in August.
42. IDENTIFICATION OF BRAIN METASTASIS VULNERABILITIES USING METPLATFORM
Authors: Zhu Lucía , Yebra Natalia , Retana Diana , Blanco-Aparicio Carmen , Martínez Sonia , Soffietti Riccardo , Bertero Luca , Cassoni Paola , Weiss Tobias , Muñoz Javier , Manuel Sepúlveda Juan , Pérez-Núñez Ángel , Hernández-Laín Aurelio , Toldos Óscar , Caleiras Eduardo , Nör Carolina , Taylor Michael D , Weller Michael , Pastor Joaquín , Valiente Manuel 
Published: August 2020

Abstract
The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. In this study, we report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures). We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. Debio-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, we have also used METPlatform to perform unbiased proteomics of brain metastases in situ. By applying this analysis to brain metastases treated with the chaperone inhibitor, we uncovered non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.
51. BRAIN METASTASES FROM ENDOMETRIAL CARCINOMA: TUMOR GENETIC ALTERATIONS IN A CASE SERIES AND META-ANALYSIS
Authors: Chapman Emily K , Tsankova Nadejda , Sebra Robert , Germano Isabelle M 
Published: August 2020

Abstract

INTRODUCTION
Endometrial carcinoma (EC) is the most common gynecologic malignancy in the world. While most patients (80%) can be cured with a hysterectomy, the remaining 20% patients who are diagnosed with advanced or recurrent disease have worse survival rates and limited adjuvant treatment options. Discovery of novel target(s)/pathway(s) is needed for better understanding of the pathogenesis and treatment development for this disease. The aim of this study is to review clinical characteristics and genetic signatures of histologically proven EC brain metastasis (BM).

METHODS
For the period 2000–2019 the medical records of patients with histological diagnosis of EC BM at our Institution were reviewed. Data were collected and analyzed for age, time interval between EC and EC BM diagnoses, tumor molecular and genetic signatures, and outcome. Immunohistochemistry and sequencing performed as published. A meta-analysis was also performed for the same time period. Data presented as mean+SD and analyzed by t-test and Chi square.

RESULTS
There were 6 BM from 5 patients meeting our cohort entry criteria and a total 123 cases reported in the literature. The mean age was 57.6 + 11.7 (range 39–69) consistent with reported data. The time interval between EC and EC BM diagnoses was 145.7 + 119.7 (range 33.1–275.7), significantly longer than reported (19.4 + 27.8; range 0–156; p&lt;0.05). All BM in our cohort were metachronous, while only 59% were in the literature. Whereas all FIGO grades are reported in the literature (I=20%; II=6%; III=42%; IV=32%), only I and III were found in our cohort (I=60%, III=40%). Tumor microsatellite instability genes MSH2 and MSH6 were intact, whereas MLH1 and PMS2 showed mutations. PD-L1 expression was low. EC BM genomic reports were not found in the literature.

CONCLUSIONS
Our study provides insight into the genomic alteration burden on EC BM. Information-driven genomic testing will continue to lead patient-centered therapeutic approaches.
53. TUCATINIB VS PLACEBO ADDED TO TRASTUZUMAB AND CAPECITABINE FOR PATIENTS WITH PREVIOUSLY TREATED HER2+ METASTATIC BREAST CANCER (MBC) WITH BRAIN METASTASES (BM) (HER2CLIMB)
Authors: Lin Nancy , Murthy Rashmi , Anders Carey , Borges Virginia , Hurvitz Sara , Loi Sherene , Abramson Vandana , Bedard Philippe , Oliveira Mafalda , Zelnack Amelia , DiGiovanna Michael , Bachelot Thomas , Chien A Jo , O’Regan Ruth , Wardley Andrew , Mueller Volkmar , Carey Lisa , McGoldrick Suzanne , An Xuebei , Winer Eric 
Published: August 2020

Abstract

BACKGROUND
HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 2019). We report results of exploratory efficacy analyses in pts with brain metastases (BM).

METHODS
All HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine. Efficacy analyses were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR-IC and DOR-IC were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy until second progression, and time from randomization to second progression or death was evaluated.

RESULTS
Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; P&lt;0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of overall death was reduced by 42% in the TUC arm (OS HR: 0.58; P=0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%) vs the control arm (20.0%). Median DOR-IC was 6.8 mo vs 3.0 mo. In pts with isolated brain progression who continued study therapy after local treatment (n=30), risk of second progression or death was reduced by 71% (HR: 0.29), and median time from randomization to second progression or death was 15.9 mo vs 9.7 mo, favoring the TUC arm.

CONCLUSIONS
In pts with previously treated HER2+ MBC with BM, TUC in combination with trastuzumab and capecitabine doubled the ORR-IC, reduced risk of IC progression or death by two-thirds and reduced risk of death by nearly half.