bluuebunny/crossref_metadata_2025_split huggingface dataset:
Wolf in sheep’s clothing: Effect of primary lung tumor cells equipped with elevated neuron-like properties on brain metastases formation.
Authors: Xu Fei , Xu Haiyan , Ying Jianming , Wang Yan 
Published: June 2023

e14009 Background: It is clinically significant to decipher the mechanisms underlying lung cancer-associated brain metastases. However, comparative studies on primary tumors between patients with and without brain metastases failed to unveil such mechanisms. Moreover, the clinical observation that the incidence of brain metastases after resection of the primary tumor was as high in lymph node-negative (non-LNM) patients as in those with lymph node metastases (LNM) challenges our established knowledge that lymph node staging correlates with distant metastases. Here, we hypothesized that tumor cells in non-LNM patients might acquire a unique mechanism to develop brain metastases. Methods: We ran whole-transcriptome sequencing and methylation sequencing on paired primary tumor and brain metastases samples from 15 NSCLC patients. We compared the differentially expressed genes (DEGs) between patients with LNM and non-LNM patients. Results: Pathway enrichment analysis showed that GO and KEGG pathways associated with neuronal transmission and synaptic signaling were upregulated in primary tumors of the non-LNM group vs. that of the LNM group. In contrast, brain metastases revealed an inversed trend of differential expression for these pathways between non-LNM and LNM groups. Exploratory validation at methylation level revealed that high expression of the neuronal transmission-associated gene GABRG3 correlated with hypomethylation of this gene (R=-0.39, p=0. 042), responsive to increased expression of GABRG3 in brain metastases. Brain metastases expressed higher neuronal transmission-related signatures than paired primary tumors. Intriguingly, this upregulation of tumor-neuron interactions was more pronounced in patients with lymph node metastases, suggesting that i) lymph node metastases might aid primary tumor to develop brain metastases by promoting the adaptation of tumor cells to the brain microenvironment, while ii) non-LNM patients already acquired neuron-like traits at primary sites, heralding the potential of brain metastases. Conclusions: The hypothetical mechanism of lymph node-negative lung cancer developing brain metastases might be that these tumor cells acquired properties of brain cells as early as in primary sites, masking themselves as ‘sheep’ to communicate with the host’s brain cells, and eventually unmasked as ‘wolf’: brain metastases. Further functional studies are warranted to validate this hypothesis.
Pattern of failure and re-irradiation for stereotactic radiotherapy treated brain metastases from non-small cell lung cancer (NSCLC).
Authors: Xu Dayu , Mao Jiuang , Ni JianJiao , Zhu Zhengfei 
Published: June 2023

e14010 Background: Hypofractionated stereotactic radiotherapy (SRT) has been increasingly used for brain metastases (BMs) from non-small cell lung cancer (NSCLC). However, the prognostic factors, pattern of failure and clinical utility of re-irradiation for these patients remain have not been fully understood. Methods: Metastatic NSCLC patients receiving SRT that covering all of the intracranial tumor lesions and without prior whole brain radiotherapy (WBRT) were retrospectively enrolled. Local recurrence free survival (LRFS), intracranial progression free survival (iPFS) and overall survival (OS) were calculated from the initiation of SRT. Post intracranial progression survival (OS2) was measured from the initial intracranial disease progression. Results: From 2018/07 to 2022/05, 218 patients were identified, with 142 (65.1%) having only one BM and 76 (34.9%) harboring 2-5 BMs. With a median follow-up of 31.1 (range, 1.0-44.6) months, median LRFS, iPFS and OS was 39.1, 26.6 and 31.1 months, respectively. No statistical difference of LRFS, iPFS and OS were found between patients with different numbers of BM. Nevertheless, patients receiving concurrent systemic therapy had significantly longer LRFS (HR=0.35, p=0.002), iPFS (HR=0.57, p=0.044) and OS (HR=0.37, p=0.001), when compared with those receiving SRT alone. By now, intracranial disease progression (iPD) was documented in 59 patients, with original site PD (OPD), new site PD (NPD) and both sites PD (BPD) occurring in 20 (33.9%), 17 (28.8%) and 22 (37.3%), respectively. Among the 59 patients, 19 (32.2%) received second-course SRT (re-SRT) targeting the intracranial progressive tumor lesions and re-SRT led to improved OS2 (22.7 vs 12.1 months, HR=0.29, 95%CI 0.08-0.97, p=0.045), which remained as an independent prognostic factor after multiple-variate Cox analyses. Conclusions: The status of systemic therapy, but not the number of BMs, may impact the survival outcomes of SRT-treated BMs from NSCLC. Some patients may benefit from re-SRT, which warranted future validation.
Predicting survival and prognosis of postoperative breast cancer brain metastasis: A population-based retrospective analysis.
Authors: Yan Nie , Zinan Lu , Sun Gang 
Published: June 2023

e14011 Background: The study aimed to construct a novel predictive clinical model to evaluate the overall survival (OS) of patients with postoperative brain metastasis of breast cancer (BCBM) and validate its effectiveness. Methods: From 2010 to 2020, a total of 310 female patients with BCBM were diagnosed in The Affiliated Cancer Hospital of Xinjiang Medical University, and were randomly assigned to the training cohort and the validation cohort. Another 173 BCBM patients were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database as an external validation cohort. In the training cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to determine the fundamental clinical predictive indicators and the nomogram was constructed to predict OS. The model capability was assessed using receiver operating characteristic, C-index, and calibration curves. Kaplan–Meier survival analysis was performed to evaluate clinical effectiveness of the risk stratification system in the model. The accuracy and prediction capability of the model were verified using the validation and SEER cohorts. Results: LASSO Cox regression analysis revealed that lymph node metastasis, molecular subtype, tumor size, chemotherapy, radiotherapy, and lung metastasis were statistically correlated with BCBM. The C-indexes of the survival nomogram in the training, validation, and SEER cohorts were 0.714, 0.710, and 0.670, respectively, which showed good prediction capability. The calibration curves demonstrated that the nomogram had great forecast precision, and a dynamic diagram was drawn to increase the maneuverability of the results. The R showed that the OS of low-risk patients was considerably better than that of high-risk patients ( P <0.001). Conclusions: The nomogram prediction model constructed in this study has a good predictive value, which can effectively evaluate the survival rate of patients with postoperative BCBM.
Rates of hematologic toxicity in WBRT vs SRS.
Authors: McCalla Aliah , Upadhyay Rituraj , Perlow Haley Kopp , Raval Raju R. , Blakaj Dukagjin , Grecula John C. , Palmer Joshua David , Thomas Evan Marshall 
Published: June 2023

e14014 Background: Whole brain radiotherapy (WBRT) has historically been a standard of care in patients with multiple brain metastases. Studies show WBRT may be associated with a transient detriment in hematological parameters because of exposure to a larger proportion of circulating lymphocytes, platelets and hematopoietic cells within the bone marrow of the cranium. We tested the hypothesis that stereotactic radiotherapy (SRS) has reduced hematologic toxicity in patients compared to WBRT. Methods: We retrospectively identified 100 patients treated for brain metastasis, with either SRS or WBRT from 2016 to 2019, and queried their pre- and post-treatment hematological parameters including hemoglobin, total white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count, and platelet count. CTCAE v5.0 was used for grading hematologic toxicities. Serial values were compared by treatment type and controlled for age, gender, & systemic therapy. Student t-test was used for intergroup comparison and p-value <0.05 was considered significant. Results: Of 100 patients, median brain metastases was 3 (range 1-22), 51 received SRS and 49 received WBRT. We observed that patients treated with WBRT had a significantly higher post-treatment reduction in platelet count (-51.2 vs 9.8; p=0.001) and higher incidence of any grade thrombocytopenia (31.2% vs 10%; p=0.019) compared to patients treated with SRS. We also noted that compared with SRS, WBRT was associated with a higher post-treatment reduction in circulating lymphocytes (-0.80 vs 0.14; p = 0.071) and higher incidence of G3+ lymphopenia (43.2% vs 22.2%; p=0.07). Numerical incidence of any G3+ hematological toxicity was also higher in the WBRT group but the difference was not statistically significant (40% vs 28%, p=0.162). Hemoglobin count, WBC, and ANC were not meaningfully different pre- and post-treatment for either group. Conclusions: WBRT results in an increased amount and duration of radiation exposure to circulating intracranial blood volume. In our study, patients treated with WBRT experienced higher rates of clinically significant lymphopenia & thrombocytopenia compared to patients treated with SRS. In addition to the cognitive benefits of SRS compared to WBRT, there may be significant hematologic benefits as well. Further studies are warranted to clarify and validate these findings. [Table: see text]
Use of proton pump inhibitors (PPI) in glioblastoma (GBM) and relationship to overall survival in a national real-world evidence (RWE) database.
Authors: Castro Michael P , Quinn Jameson , Wasserman Asher , Shapiro Mark Adam , Stuhlmiller Timothy Joseph , Kesari Santosh 
Published: June 2023

e14027 Background: Aldehyde dehydrogenase-1A1 ( ALDH1A1) mediates therapy resistance and poor prognosis in multiple cancers. In GBM, ALDH1A1 expression above vs. below the mean is associated with a significant reduction in survival.1 ALDH enzymes activate transcriptional programs that induce the cancer stem cell phenotype, detoxify anticancer drugs, and function as antioxidants by reversing lipid peroxidation and etheno-DNA adducts, thus conferring chemotherapy and radiation resistance. PPI have been shown to increase enzyme activity of ALDH1A1 up to 6-fold, suggesting a potentially hazardous effect on tumor biology and survival. However, no prospective randomized data are available to address these concerns. Thus, we turned to XCELSIOR, an observational database that prospectively collects medical records including medication usage. Methods: Patients with GBM were e-consented to XCELSIOR ( NCT03793088 ), a nationwide observational research protocol that leverages patient consent to permit gathering of medical records from all sites of care. Clinical data were abstracted from medical documents into a central EDC system, source-verified, and standardized to generate comprehensive longitudinal histories for aggregate analysis. Identified patient records permitted the definitive identification of dates of diagnosis and death. Overall survival (OS) was calculated and stratified based for PPI exposure, extent of surgical resection (EOR), and MGMT methylation status. Results: XCELSIOR contained 320 GBM patients from 222 treatment sites. We stratified patients based on exposure to PPI and assessed median OS (mOS). For the entire population, mOS was substantially better for patients not receiving PPI. (TABLE) The 5-yr survival was 29.9% [21.0 – 42] and 6.6% [1.4 – 32.0] for patients not receiving vs. receiving PPI. In a multivariate analysis considering EOR and MGMT methylation, PPI exposure yielded a hazard ratio (HR) of 1.57 (p=0.009). For the interaction of m-MGMT and PPI exposure together, the HR is 2.63 (p=0.043), significant as the HR of m-MGMT alone is 0.40 (p=0.0028). Conclusions: In this RWE dataset, PPI use in GBM appeared detrimental to survival. This is strongly consistent with the hypothesis that PPI antagonizes chemotherapy. Additionally, use of PPI appeared to completely abrogate the survival benefit of chemotherapy associated with methylated-MGMT. While we recognize the utility of PPI in managing acute UGI bleeding, these data suggest avoiding PPIs in GBM patients. 1) Schmidt-Graf F, et al. Neuro Oncol. 2012;14(12):1452–1464. [Table: see text]
Feasibility and utility of the custom RNA-seq for the identification of therapeutic targets and diagnostic biomarkers in glioma.
Authors: Takahashi Masamichi , Kohsaka Shinji , Ichimura Koichi , Mano Hiroyuki , Narita Yoshitaka 
Published: June 2023

e14029 Background: The detection of novel therapeutic targets is increasingly important in oncology. The Todai OncoPanel (TOP) RNA panel is a custom target RNA-seq using the junction capture method to maximize the sensitivity in detecting of known 456 fusion gene transcripts, which is scheduled to be approved for clinical application in Japan in April 2023. Above, TOP RNA panel interrogates aberrantly spliced transcripts and analyzes the expression profiles of 1,390 genes. Malignant brain tumors, including gliomas, require various molecular profiles to be classified based on the latest WHO classification criteria, while their poor prognosis also necessitates new therapeutic targets. In this study, we aimed to classify gliomas and identify the molecular targets by TOP RNA panel. Methods: Among 131 frozen tumor samples of malignant gliomas, 124 samples passed quality control for further validation and were subjected to TOP RNA panel to classify based on the molecular profiles and to identify the molecular targets. Fusion detection and RNA expression analysis were conducted with the original pipeline. Cluster analysis and Gene Set Enrichment Analysis (GSEA) were performed to identify gene sets specific for individual subtypes. Copy numbers of tyrosine kinase genes, MDM2 and CDK4 were evaluated by digital droplet PCR (ddPCR). Results: Among 58 cases of glioblastoma, gene fusions were detected in 11 cases (19.0%) including novel MET fusions, and overexpression of seven tyrosine kinase genes were observed in 21 cases (36.2%). Of the 34 overexpressed genes, gene amplification was observed in 17 genes (50%) by ddPCR. In contrast to IDH-wildtype glioblastoma, IDH-mutant tumors including astrocytomas and oligodendrogliomas hardly harbored fusion genes or gene overexpression. GSEA to compare astrocytomas and oligodendrogliomas identified that the gene sets related to 1p36 and 19q were relatively enriched in astrocytoma, suggesting that regional genomic DNA copy number alterations can be evaluated by gene expression analysis. Conclusions: TOP RNA panel is utilized not only for the detection of molecular targets but also for the molecular classification of glioma, both of which is essential for providing treatments optimized for the individual patients.
Incidence of non-canonical IDH mutations and IDH co-mutations in a multicenter prospective study of patients with glioma.
Authors: Cabezas-Camarero Santiago , Pérez-Alfayate Rebeca , García-Barberán Vanesa , Gandía Marisa , García-Feijoo Pablo , López-Cade Igor , Casado-Fariñas Isabel , Garcia-Conde Mario , Sanchez-Medina Yanire , Ceron Maria Angeles , Sotelo Lezama Miguel , Pérez-Segura Pedro 
Published: June 2023

e14033 Background: IDH-mutant tumors are a distinct disease entity accounting for one third of gliomas with a more favourable prognosis despite still harboring high morbidity and mortality rates. Most IDH mutations (muts) in gliomas group at R132/R172 hotspots in IDH1/IDH2, respectively. Our aim was to study IDH non-canonical muts and IDH co-mutations (co-muts) since the evidence is still limited. Methods: Prospective study of patients (pts) with gliomas at 4 third-level hospitals in Spain (Hospital Clinico Universitario San Carlos, Hospital Universitario La Paz, Hospital Universitario de Canarias, Hospital Universitario Nuestra Señora de la Candelaria). High throughput next generation sequencing (NGS) using a customized gene panel ((Illumina, Inc) including IDH1 and IDH2 was used in FFPE and/or fresh tumor samples, and run in an Illumina MiSeq instrument (Illumina, Inc). Only pathogenic mutations were considered as valid. Clonal IDH (cIDH) muts were defined as those with a MAF ≥ 1% and subclonal IDH (scIDH) muts as those with a MAF < 1%. Results: Between February 2017 and February 2021, 49 glioma pts enrolled and sequenced for IDH1/IDH2 tumor muts. Median age 51 (Min-max: 20-78). WHO 5th Ed (n = 42): IDH-MUT astrocytoma (n = 14), IDH-MUT oligodendroglioma (n = 7), IDH-WT glioblastoma (n = 21). 37/49 pts (75.5%) presented cIDH and/or scIDH muts, of which 21 pts (43%) harbored cIDH muts in IDH1 (R132H (n = 17), R132C (n = 1), R132G (n = 1), R100Q (n = 1), G161R (n = 1)) and in IDH2 (R140W (n = 1), R140Q (n = 1)). In 17/21 pts (81%) cIDH-mut MAF ≥ 10%. Of 21 cIDH-mutant pts, there were IDH co-muts in 11 pts (52%). Of these 11 pts, IDH co-muts were scIDH in 91%: #2 (IDH1 R100Q/G161R), #3 (IDH1 R132H/R119Q/G161R), #4 (IDH1 R132H/R132C; IDH2 R172G/R140Q), #11 (IDH1 R132H/R132C), #21 (IDH1 R132H/G161R; IDH2 R140Q), #23 (IDH1 R132H/R132C), #31 (IDH1 R132H/G161R; IDH2 R140Q/P162L), #32 (IDH1 R132H/R100Q), #33 (IDH1 R132H/R100Afs*29/I130V), #37 (IDH1 R132H; IDH2 R159H), #40 (IDH1 R132H; IDH2 R172G). Median overall survival (OS) longer in cIDH-mut vs IDH-wt (159 vs 16 months, P = 0.000). No difference in OS in: cIDH vs cIDH + scIDH (NR vs 67 m, P = 0.437), in scIDH vs cIDH (79 vs 159 m, P = 0.111), and scIDH vs IDH-wt (79 vs 12 m, P = 0.229). Conclusions: Subclonal (defined as MAF < 1%) canonical and non-canonical IDH-mutations and co-mutations occur frequently in gliomas. This may have implications for the design of future clinical trials and in the development of IDH inhibitors including the anticipation of potential resistance mechanisms.
A multicenter retrospective study of timing of chemoradiation in high-risk, grade 2, IDH-mutated astrocytoma.
Authors: McGranahan Tresa , Lanman Tyler Ashford , Densmore Isabella 
Published: June 2023

e14035 Background: Patients with Grade 2 IDH mutated astrocytoma that have residual disease after surgery are characterized as high risk. There is limited data to guide timing of treatment for these patients so treatment guidelines recommend either adjuvant chemoradiation or observation delaying adjuvant treatment until disease progression (OBS). This study sought to evaluate the clinical characteristics and survival of patients with Grade 2 IDH mutated astrocytoma treat with adjuvant temozolomide (TMZ) based chemoradiation (tRT) compared to patients treated with observation following surgery. Methods: We conducted a multicenter retrospective study of patients with histologic grade 2 IDH mutated astrocytoma treated at the University of Washington and Stanford Medical Center. To evaluate the impact of treatment, tRT was defined as treatment decision at time of diagnosis to treat with radiation in combination with concurrent and or adjuvant TMZ. Extent of resection and progression were determined based on the treating neuro-oncologists notes. Survival probability, overall survival (OS) and time to first progression (PFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in GraphPad Prism. Results: A total of 115 patients were identified with a median follow up of 6.54 years (y). For the whole cohort, median overall survival (mOS) was 15.5y and median progression free survival (mPFS) was 4.9y. For the whole cohort, 29 patients were treated with tRT and 58 with OBS. tRT improved PFS compared to OBS (p=0.044) with mPFS 6.17y v. 3.58y. There was no difference in OS (p=0.11) as the mOS for tRT was 12.8y v. 15.5y. For the patients with residual disease after surgery, 24 patients were treated with tRT and 26 with OBS with a median follow up of 5.3y. Treatment with tRT trended towards improved PFS (6.2y) compared to OBS (3.5y) (p=0.061). There were no significant difference in demographics of these high risk patients. For OBS patients, 6 had tRT at progression in the range of 0.9y to 25.4y and median time of 2.4y. Conclusions: This multicenter retrospective study found that for Grade 2 IDH mutated astrocytoma, tRT treatment following surgery with residual disease improved PFS but did not impact mOS. However in high risk patients, tRT did not impact either PFS or OS. This study further confirmed the protracted natural history of this disease and supports observation as a treatment option for patients with Grade 2 IDH mutated astrocytoma, even for high risk patients who underwent biopsy or subtotal resection. [Table: see text]
When to treat: A multicenter retrospective study of timing of radiation therapy in 1p19q co-deleted, IDH mutated oligodendrogliomas.
Authors: Densmore Isabella , Lanman Tyler Ashford , McGranahan Tresa 
Published: June 2023

e14036 Background: Oligodendrogliomas, molecularly defined by IDH mutation and 1p19q codeletion, have a protracted natural history and are more chemoresponsive compared to astrocytomas. While the addition of chemotherapy to radiation improves survival, if chemoradiation should be initiated following diagnosis or at progression remains unknown. Given the potential for early and late radiation-related toxicity, a careful evaluation of timing of treatment is critical to optimize treatment guidelines for oligodendroglioma. We aimed to evaluate the benefit of initial adjuvant radiation therapy (RT) on survival in patients with oligodendrogliomas. Methods: We conducted a multicenter retrospective study of patients treated at the University of Washington and Stanford Medical Center with oligodendrogliomas using both 1p19q codeletion and IDH mutation to define the diagnosis, reflecting the World Health Organization 2021 diagnostic criteria. Survival probability, overall survival (OS) and time to first progression (PFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in GraphPad Prism. Propensity Score Matching was completed using XLSTAT. Results: 243 patients were identified as oligodendroglioma and 229 had treatment and survival data available with a median follow up of 5.8 years(y). Median OS was 22.5y and median PFS was 5.35y. 110 patients were treated with adjuvant radiation (aRT) within 1y of diagnosis and 119 underwent observation or chemotherapy alone (delayed RT, or dRT). PFS was comparable between aRT (7.7y) and dRT (4.6y) but OS was longer in dRT (27.8y) than aRT (13.7y) (p < 0.001). Given imbalance in baseline characteristics, propensity score matching was used to adjust for high risk factors of age, grade and presence of residual disease resulting in 63 pairs. In this matched cohort, aRT prolonged PFS (aRT = 7.75y v. dRT = 4.33y, p = 0.006) however dRT still demonstrated a survival benefit (p = 0.017). 59 dRT patients were treated with RT at progression and also had longer medan OS of 22.6y compared to 13.7y in the aRT (p = < 0.0001). The time to RT for this cohort ranged be 1.1-19y. Conclusions: To our knowledge this is the largest retrospective study of molecularly defined oligodendrogliomas that includes treatment information. This study confirms the protracted natural history of this disease. In our multi-institution cohort, early adjuvant radiation therapy may increase PFS but was not found to prolong OS. Prospective studies evaluating the timing of treatment in patients with oligodendroglioma are needed. [Table: see text]