bluuebunny/crossref_metadata_2025_split huggingface dataset:
P17.02.B BMSCOPE: A SCOPING REVIEW TO CHART THE EVOLVING CLINICAL STUDY LANDSCAPE IN BRAIN AND LEPTOMENINGEAL METASTASIS
Authors: Heywood R , Cheng V , Zakaria R , Burger R , Zucker K , Kannan S , Putra M , Fitzpatrick A , Doherty G , Sanghera P , Jenkinson M , Palmieri C 
Published: October 2024

Abstract

BACKGROUND
Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises BM/LM clinical studies published globally between 2010 and 2023.

MATERIAL AND METHODS
Eleven electronic databases were searched on 21 June 2021, with an updated search on 21 February 2023. Clinical studies were included if they involved the investigation of a therapeutic intervention in patients with BM and/or LM, and a reported patient outcome. Study-level data was extracted by study authors, including study type, date of publication, country of data collection, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention

RESULTS
48222 studies were identified from the electronic search and 4921 unique studies were eligible for analysis, with increasing numbers of studies (and international collaborations) through the study period. 627 of these publications were clinical trials. Over the study period there was a shift towards later stage clinical trials, predominantly trials of systemic therapy that included BM/LM patients. Despite this, only 29.2% reported intracranial-specific outcomes.

CONCLUSION
In this comprehensive analysis of the BM/LM literature, we chart the evolving landscape of studies involving this previously clinically excluded population. Given the increasing clinical research activity, particularly late-stage systemic therapy trials, it is imperative that consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of intracranial efficacy
P17.08.B EFFICACY AND SAFETY OF POSTOPERATIVE HYPOFRACTIONATED RADIOTHERAPY FOR RESECTED BRAIN METASTASES: INSIGHTS FROM A SINGLE-CENTRE EXPERIENCE
Authors: Lucas Calduch A , Macià Garau M , García Expósito N , Plans Ahicart G , Rosselló Gómez A , Fernández Coello A , Vidal Sarro N , Modolell Farré I , Sancho Kolster I , Majós Torró C , Pons Escoda A , Simó Parra M , Velasco Fargas R , Ruíz Domínguez M , Alonso Becerra M , Cifre Serra P , Bruna Escuer J 
Published: October 2024

Abstract

BACKGROUND
The addition of radiotherapy (RT) improves local control after surgical resection of brain metastases (BM). The classical whole brain RT has been replaced by different types of focal irradiation. Hypofractionated stereotactic radiotherapy (HFSRT) is an effective option, but the procedure implies several uncertainties related to the volumes contouring, that may generate the risk of local control fail and/or the development of radionecrosis (RN) of the cavity wall.

MATERIAL AND METHODS
We have retrospectively reviewed the outcome of patients with surgically resected BM that have been adjuvantly treated with HSRT in our centre, during the period from 2015 to August 2023.

RESULTS
83 patients have been identified. Median age was 58 (34-79). Males comprised 54% and 46% were females. Lung cancer was the most frequent primary tumour (51%), followed by breast (17%) and melanoma (15%). BM diagnose was synchronous to the primary in 36% of patients. The targeted BM was single in 87% of cases, and its median maximum diameter was 36 mm (13-75). Surgery was complete in 82% of cases. Clinical conditions before RT were favourable in 87% of patients (Karnofsky index ≥70) and DS-GPA (diagnosis-specific graded prognostic assessment) was ≥3 in 47%. Different ways of contouring the planning target volume (PTV) were identified, being the addition of 2 mm to the cavity the most frequent (44%). The median PTV was 29,9 cm3 (1,17-138,8). Regarding radiotherapy scheme, 27 Gy in 3 fractions were prescribed in 36% of patients; however, 30 Gy in 5 or 6 fractions were also frequently used (32%). Tolerance was excellent, except for one patient with Grade 3 seizures. The median interval between surgery and HFSRT was 56 days (r 45-69). After a median follow-up of 19 months, local control in surgical bed was obtained in 92,7% and 89,2% of cases at 1 and 2 years respectively. RN was observed in 15,6% of cases, with only 2,4% of grade 3. Cranial and extracranial progressions were seen in roughly half of patients (53% and 53,7% respectively). Specifically, leptomeningeal spread was seen in 26,5% of patients. Overall survival was 54% at 2 years.

CONCLUSION
HFSRT appears as a highly effective option to ensure local control after surgery in BM. Despite the uncertainties related to contouring and the high number of large cavities, the use of fractionated schemes allows a low incidence of serious RN.
P17.10.A GENOMIC PROFILING OF CEREBROSPINAL FLUID CTDNA TO CHARACTERIZE MOLECULAR FEATURES AND MONITOR INTRACRANIAL RESPONSES OF OSIMERTINIB-RESISTANT NON-SMALL CELL LUNG CANCER PATIENTS WITH LEPTOMENINGEAL METASTASES
Authors: Li X , Hua Y , Xin Y , An J , Ding X , Wei F 
Published: October 2024

Abstract

BACKGROUND
Leptomeningeal metastasis (LM) indicates an unfavorable prognosis in non-small cell lung cancer (NSCLC). Due to the blood-brain barrier, plasma is not an ideal medium to evaluate osimertinib resistance mechanisms in patients with LM. This study aimed to use cerebrospinal fluid (CSF) as a source of ctDNA for characterizing molecular features and monitoring intracranial responses from patients with leptomeningeal metastases who progressed on osimertinib.

MATERIAL AND METHODS
From Jan 2020 to Nov 2022, 65 patients with advanced NSCLC, including 30 osimertinib-treated patients, 7other TKI-treated patients, and 28 treatment-naïve patients, in Beijing Tiantan Hospital were enrolled in this study. CSF obtained via lumbar puncture was used for targeted sequencing and cytologic analysis. In parallel, paired plasma from 37 patients was also subjected to targeted sequencing.

RESULTS
Among 65 patients, the overall positive rate of CSF ctDNA was 77% (50/65), 94% (32/34) in patients with LM, and 58% (18/31) in patients with brain parenchymal metastases (p=0.0008). EGFR alterations were present in the CSF of 96% of patients who progressed on osimertinib, including L858R (64%), copy number gain (29%), exon 19 deletion (18%), T790M (11%), L861Q (7%), G719X (7%) and L747X (7%). EGFR-independent intracranial resistance mechanisms identified in CSF included activation in phosphatidylinositol 3-kinase (PI3K) pathways, RAS-mitogen-activated protein kinase (MAPK), cell-cycle gene alterations, MET amplification, oncogenic fusions. The VAF identified by CSF ctDNA was also higher than that of plasma ctDNA (15.5% versus 4.6%, P&lt;0.001). In patients with LM, 75% of alterations were detected exclusively in CSF ctDNA and 13% in plasma ctDNA. The higher proportion of CSF ctDNA private mutations observed in patients with LM compared to those with PM. Serial surveillance of CSF ctDNA in 6 cases of LM patients treated with osimertinib found that the VAF of CSF ctDNA showed a highly consistent trend with the tumor cell fraction of cytology.

CONCLUSION
For EGFR-mutated NSCLC patients with LM, liquid biopsy of CSF is more sensitive than plasma to characterize osimertinib-resistant mechanisms and guide follow-up treatment. Serial surveillance of CSF ctDNA dynamics may reflect the intracranial tumor responses, which still needs to be validated in a large sample size.This study was supported by Beijing Municipal Education Commission-Beijing Natural Science Foundation Union Program(KZ202010025046), Beijing Natural Science Foundation (NO. 7242007) and Beijing Xisike Clinical Oncology Research Foundation(Y-2021AST/zd-0127).
P17.12.B LEPTOMENINGEAL DISEASE FOLLOWING POSTOPERATIVE RADIOSURGERY IN RESECTED BRAIN METASTASES: LONG TERM FOLLOW UP OF A PHASE 2 STUDY
Authors: Navarria P , Pessina F , Clerici E , Bellu L , Politi L , Vernier V , Raspagliesi L , Bono B , Franzini A , Scorsetti M 
Published: October 2024

Abstract

BACKGROUND
Brain metastases (BMs) affect about 20-40% of patients with solid primary tumors, and as many as 25% of patients will harbor large BMs. Surgical resection followed by postoperative stereotactic radiosurgery has become the standard modality to treat large BMs, given the ability to obtain a satisfactory local control with neurocognitive preservation. Notwithstanding the excellent outcome of a combined treatment approach, one concern is the potential risk of developing leptomeningeal disease (LMD) occurring in up to 30% of patients receiving surgical resection followed by postoperative SRS. We evaluated LMD in patients enrolled in prospective phase 2 study treated with surgery followed by hypofractionated radiosurgery (HSRS) on the tumor bed in oligometastatic patients with single large brain metastases (BMs). Local control (LC), brain distant failure (BDF), overall survival (OS), and prognostic factors related to LMD were analyzed too.

MATERIAL AND METHODS
A retrospective review of patients treated into a prospective phase 2 study with surgery followed by HSRS on the tumor bed from June 2015 and May 2018 has been performed. Patterns of LMD were determined radiographically based on the first MRI at which LMD was diagnosed. Prognostic factors for LMD have been evaluated as well. LC was assessed using Response Assessment in Neuro-Oncology criteria, BDF defined as the appearance of new BMs in other brain sites in respect to the treated ones. OS was calculated from BMs treatments. Cause of death was defined as neurologic in case of diffuse brain or meningeal progression, and systemic in case of diffuse extracranial progression with controlled brain disease.

RESULTS
One hundred and one patients were included in the present analysis. The median follow up time for the whole cohort was 25 months (range 3-109 months) and 79 months (range 67-91 months) for alive patients. LMD has been recorded in 20 (19.8%) patients at a median time of 9 months (range 3-47 months) from surgery. For patients with LMD the median OS time, 6-month, 1-year, and 2-year OS rates were 16 months, 95%, 75%, and 20%, respectively compared to 20 months, 93%, 80.6%, and 38.7%, respectively for those with BDF only without LMD. According to logistic regression analysis, the infratentorial site (p=0.04) and meninges not surgically removed (p=0.01) influenced the development of LMD. At long term follow up the 2, 5 years LC, BDF, and OS rates 87%, 78%; 50.4%, 56.8%; 49.5%, 23.8% respectively. The occurrence of LMD significantly influenced OS (p=0.01).

CONCLUSION
Surgery followed by HSRS on the tumor bed is an effective and safe treatment approach. LMD conditioned a worse outcome. In the future the employ of preoperative HSRS could represent a valid approach to potentially reduce this adverse event.
P17.15.A PATTERNS OF CARE AND OUTCOMES IN BRAIN METASTASES FROM BILIARY TRACT CANCERS IN THE UNITED STATES: A REAL-WORLD ANALYSIS
Authors: Jayram D , Ozair A , Ahmad S , Bellur S , Frias Perez N , Podder V , Ahluwalia M 
Published: October 2024

Abstract

BACKGROUND
Biliary tract cancers (BTC) are frequently diagnosed late in their disease course. Brain metastases (BM)s from BTC, while rare, lack contemporary literature. This study describes patient characteristics, patterns of care, and outcomes of BM from BTCs in the United States (US).

MATERIAL AND METHODS
This retrospective study was conducted following ESMO ‘Guidance for Reporting Real-World Oncology Evidence’ (GROW) guidelines using the National Cancer Database, a nationally representative US database capturing &gt; 70% of oncology outcomes, for BTC BMs from 2010-2020. Patient attributes and patterns of care were analyzed with descriptive statistics. Kaplan-Meier estimation was used for median overall survival (mOS, 95% CI).

RESULTS
Of 88,274 BTC patients, 0.16% had BM (n=138). Median age was 65 years (IQR 58-74). Of patients with BMs, 50.7% were female. 78.26% were White, 13.04% Black, 1.45% Asian. 16.7% were Hispanic. Incidence proportion of patients with BMs increased from 5.8% (n=8) in 2010 to 12.32% (n=17) in 2020. 50.72% (n=70) had Medicare, 13.04% (n=18) Medicaid, 29.7% (n=41) were privately insured, and 4.4% (n=6) were uninsured. 46.4% (n=64) cases originated from the extrahepatic bile duct, 8.7% (n=12) in the ampulla of Vater, 2.9% (n=4) in the overlapping area of biliary tract, and 34.8% (n=58) were not specified. 41.3% (n=57) received no treatment. mOS for the whole cohort was 2.2 months (CI 0.1-16.9). mOS for treated patients was 4.0 months (CI 3.1-6.9). 41.3% (n=57) received chemotherapy, 23.9% (n=33) radiation to the brain, 14.5% (n=20) radiation to other sites, and 2.2% (n=3) surgery. Among chemotherapy recipients (n=57), 78.9% (n=45) received multiagent therapy, 15.8% (n=9) received single-agent therapy, and 5.3% (n=3) lacked specified agent numbers. Of the patients who underwent cranial radiation, 69.7% (n=23) received stereotactic radiosurgery and 30.3% (n=10) received whole brain radiation. 13.7% (n=19) received both cranial radiation and chemotherapy, and 0.7% (n=1) received cranial radiation, surgery, and chemotherapy.

CONCLUSION
Patients with BM from BTCs have a dismal prognosis. Clinical trials on efficacious therapies are urgently warranted for these patients.
P17.18.B RECURRENT PINEOBLASTOMA WITH LEPTOMENINGEAL METASTASES
Authors: White J D , Baykal D , Webb M J , Neth B , Mahajan A , Kowalchuk R , Schwartz J , Sener U 
Published: October 2024

Abstract

BACKGROUND
Pineoblastoma is an aggressive, rare tumor of the pineal gland. Due to rarity of pineoblastoma, no large-scale prospective clinical trial data is available to guide clinical practice. Patients often receive treatment based on approaches to other high-grade embryonal central nervous system (CNS) tumors such as medulloblastoma. Multimodality treatment typically consists of maximal surgical resection followed by radiation therapy and chemotherapy. Despite treatment, recurrence is common and five-year survival rate is 60-70%. Pineoblastoma can disseminate through the leptomeninges, which is associated with poor survival. No therapy is known to confer a survival benefit in the setting of leptomeningeal disease (LMD) related to pineoblastoma.

MATERIAL AND METHODS
We report radiographic response and longer than expected survival for a patient with LMD related to pineoblastoma treated with single-agent temozolomide chemotherapy.

RESULTS
A 22-year-old male with a history of pineoblastoma presented with periodic headaches and leptomeningeal enhancement on surveillance imaging. 5 years prior to presentation (age 17), he was initially diagnosed with pineoblastoma after gross total resection followed by treatment with proton craniospinal radiation and adjuvant carboplatin/vincristine chemotherapy. Surveillance craniospinal MRIs identified diffuse leptomeningeal enhancement involving the posterior fossa and diffusely throughout the spine and lumbosacral nerve roots. While cerebrospinal fluid (CSF) cytology was negative for tumor cells on three separate occasions, CSF cell-free DNA (cfDNA) analysis isolated tumor DNA. He was started on temozolomide chemotherapy with near complete resolution of leptomeningeal enhancement on MRI after 2 cycles and complete resolution after 6 cycles. Treatment was well-tolerated with grade 1 fatigue as the only toxicity. Patient remains alive 20 months after initial diagnosis of LMD with resolution of headaches and durable radiographic response.

CONCLUSION
This case highlights utility of CSF cfDNA as a companion tool for diagnosis of LMD. Durable clinical and radiographic response achieved suggests temozolomide can be considered as a salvage treatment option for recurrent pineoblastoma with LMD.
P17.19.A RESECTION OF BRAIN METASTASES WITH FLUORESCENCE GUIDANCE - COMPARISON BETWEEN SODIUM-FLUORESCEIN AND 5-ALA
Authors: Neumeister A , Meier T , Lawson McLean A C , Andreas N , Senft C 
Published: October 2024

Abstract

BACKGROUND
Complete neurosurgical resection is an integral part of treatment in cancer patients with metastatic brain disease. The distinction between metastatic and healthy brain tissue is of critical importance in this context. Whereas the use of 5-ALA fluorescence has been established for gliomas, reportedly not all metastases enhance with 5-ALA. Therefore, resection using sodium-fluorescein (Na-Fl) may be more helpful to delineate tumors and their margins.

MATERIAL AND METHODS
We performed a retrospective analysis of resected brain metastases (BM) and use of intraoperative fluorescent agents from 2021 to date. The surgical reports were analyzed whether 5-ALA or Na-Fl was used and if fluorescence was visible using the specific microscope filter. The histopathological findings were then documented. Finally, a chi-square independence test was performed.

RESULTS
Of 56 patients with BM, Na-Fl was applied in 30 cases, whereas 26 BMs were resected with use of 5-ALA. Following Na-Fl-administration, in 2 of 30 cases, there was no visible fluorescence in the Yellow 560 nm filter (6.7 %), but fluorescence was positive in the remaining 28 metastases (93.3 %). In contrast, 5-ALA induced fluorescence in the Blue 400 nm filter was negative in 11 (42.3 %), positive in 10 (38.5 %). In 5 cases, the fluorescence pattern was not documented (19.2 %). The difference in positive fluorescence between Na-Fl and 5-ALA was statistically significant (p=0.0007).

CONCLUSION
In intracranial metastases, Na-Fl-induced fluorescence was more frequently observed in contrast to 5-ALA. Na-Fl can therefore be useful in the identification of brain metastases as well as the rapid and cost-effective differentiation of metastatic from healthy brain tissue. Further studies should be carried out to investigate whether use of Na-Fl influences the extent of resection.
P18.03.B ANTIBIOTIC EXPOSURE DURING RADIOTHERAPY FOR GLIOBLASTOMA MULTIFORME IMPACTS SURVIVAL
Authors: Main S , Swampillai A , Lavrador J , Al-Salihi O , Chia K , Brazil L , Manik V , Ching J , Clarke E , Reis Ferreira M 
Published: October 2024

Abstract

BACKGROUND
IDH wildtype Glioblastoma multiforme (GBM) is an aggressive primary brain tumour. Despite treatment with surgical resection, radiotherapy (± chemotherapy) and adjuvant chemotherapy median survival remains poor. Antibiotics influence the human microbiota and alter treatment efficacy in other tumours. This study addresses antibiotic exposure in GBM.

MATERIAL AND METHODS
A retrospective observational study based on electronic patient records March 2016-May 2022 in a large UK tertiary centre (N=234) and replicated for validation purposes in a second UK tertiary centre (N=179) over the same time period. All patients received radiotherapy 54-60Gy/30 fractions or 40Gy/15 fractions ± concurrent/adjuvant temozolomide chemotherapy. Prophylactic antibiotics with co-trimoxazole were used during concurrent chemoradiotherapy as per the Stupp protocol. Peri-operative, prophylactic and antibiotic exposures within 30 days of death were excluded. Additional antibiotic exposures were recorded from 4 weeks prior to radiotherapy to the completion/discontinuation of adjuvant temozolomide chemotherapy. Survival analysis was conducted with Kaplan-Meier methodology and Cox proportional hazard modelling using R language for statistical programming.

RESULTS
99 (42.3%) patients in the principal study cohort and 44 (31.7%) patients in the validation cohort received antibiotics. They were most commonly prescribed for respiratory infections (40.2% and 37.3%) and broad-spectrum penicillin-based (60.5% and 49.3%). There was no clear indication for prescriptions in 15.6% and 9.3% of the principal and validation cohorts respectively. Antibiotic exposure has a negative impact on survival in the principal and validation cohorts: median overall survival (mOS) 12.0 months(mo) vs 15.2 mo (P= 0.0062); mOS 12.5mo vs 19.2mo(P=0.0023). This effect is greater in those with better predictors of prognosis (i.e. MGMT promoter methylation receiving Stupp chemoradiotherapy): mOS 15.2mo vs 33.3mo (P=0.013) and mOS 9.3mo vs 27.7mo (P=0.001) in principal and validation cohorts respectively. The association of antibiotic exposure and survival compromise was resilient in multivariate analysis with established risk factors in both cohorts: hazard ratio 1.52(P=0.017) in principal cohort and 2.81(P=0.023) in validation cohort.

CONCLUSION
Antibiotic exposure reduces treatment efficacy in GBM. The human microbiome (gut/intratumoural) may well underpin the mechanism of this observed effect. Ongoing work will explore the presence and influence of the tumoural and gut microbiome in GBM. These results pose a challenge to the use of prophylactic antibiotics with chemoradiotherapy. We recommend multi-centre validation and that clinicians consider to use prophylactic antibiotics only in those with a high risk of PJP (low lymphocyte count, prolonged high dose corticosteroids).
P18.05.B ASSOCIATION OF CELLULAR DRUG RESPONSES AND METABOLIC PROFILES IN ADULT TYPE DIFFUSE GLIOMAS
Authors: Stanzer S , Bandres-Meriz J , Harbusch N , Franz J , Mahdy-Ali K , Ferreira da Silva Souza Monedeiro F , Magnes C , Zügner E , Pieber T , El-Heliebi A , Urbanic Purkart T , Wöhrer A , Prietl B 
Published: October 2024

Abstract

BACKGROUND
Functional precision medicine is the next step in individualized patient centered medicine, seeking to guide treatment based on ex-vivo drug response of patient-derived tumor cells (PDCs). In this study we aimed to evaluate the drug response (combination of potency and efficacy) to a panel of cytotoxic and targeted agents in PDCs isolated from IDH-mutant (mut) and -wild type (wt) gliomas. Next, we integrated these assessed drug responses with corresponding metabolomic tissue signatures reflecting the in-vivo metabolic profile of IDH-mut and -wt gliomas. To gain further insight into the aggressive behavior of IDH-wt tumors, we aimed to characterize clonal and sub-clonal metabolic heterogeneity within IDH-wt gliomas to uncover potential therapeutic vulnerabilities.

MATERIAL AND METHODS
The tumor tissues of patients with glioma were used for PDC isolation prepared by mechanical and enzymatic tissue dissociation. After short-term cultivation (7-14 days) under standard culture conditions, spheroids (n=50) were dissociated into a single-cell suspension and subjected to drug screening using a high throughput screening platform. The drug panel consisted of 80 chemotherapeutics and targeted drugs. Dose response curve (DRC) fitting per drug was performed and the area under the curve (AUC) was evaluated. Corresponding tumor tissues obtained from surgical resections were analyzed by HILIC-HRMS. We then correlated the metabolomic profiles with the drug response.

RESULTS
First analysis within this cohort (n =18) showed significantly lower AUC values (i.e. enhanced drug response) of panobinostat and vorinostat (HDAC inhibitors), AMG232 and RG7112 (MDM2 inhibitors), selinexor (exportin-1 inhibitor) and temsirolimus (mTOR inhibitor) in IDH-wt gliomas (all p&lt;0.05). Statistical correlation analysis between AUC values and metabolite levels showed substantially more significant correlations (criteria: |r|&gt; 0.5, p&lt;0.05) between drug responses and metabolites in IDH-wt tumors (1329 versus 926).

CONCLUSION
These first analyses showed an association between drug response and metabolism when using a holistic approach. Additionally, these results suggested a connection between metabolic pathways and drug susceptibility. In the next step, we plan to investigate the metabolic heterogeneity of IDH-wt gliomas within the tumor in more detail to find out whether there is an influence on the response to treatment.