bluuebunny/crossref_metadata_2025 huggingface dataset:
“You matter”: Patient reported outcomes on cancer disparities related to the COVID-19 pandemic.
Authors: Mohanna Mohamed , Sabbagh Saad , Dominguez Barbara , Itani Mira , Saba Ludovic , Iska Sindu , Liang Hong , Diaz Caroline , Nahleh Zeina A.
Published: June 2023

e13674

Background: Disparities in cancer care have been exacerbated by the COVID-19 pandemic. Understanding the challenges encountered by patients can help alleviate the burden of cancer and improve access to care. Methods: We recruited consecutive patients with cancer at a comprehensive academic cancer center and analyzed patient reported socioeconomic and mental health challenges, and their perception of access to care since the start of the pandemic using a modified version of the You Matter: COVID-19 Mental Health Impact Survey. The survey instrument was self-administered once from November 11, 2022 to January 12, 2023 and consisted of 21 items with questions focused on demographics, social health, telehealth attitudes, and mental health. Established patients diagnosed at the cancer center prior to the start of the COVID-19 pandemic and who are continuing care were included in the study. Results: A total of 136 participants were included in this analysis. Participants characteristics were as follows: 70% had age>65, 75% white, 70% female, 43 % had bachelor's degree or higher, 62.5% with non-private insurance, 95% maintained same insurance throughout the pandemic, and 80% had household of > 1 person. Since April 2020, 49.3% reported increased level of stress and 60.6% reported increased anxiety, stress or experience of distress as a direct result of COVID-19. Among the patients that reported they had participated in telehealth, 84.4% described it as easy and effective, and 70.6% found it either comfortable or neutral. Black participants were more likely to have less contact with providers compared to white participants (OR=5.54, p=0.0180); participants age ≥65 were more likely to report worse overall health compared to younger participants (OR=2.67, p=0.0359); male participants were more likely to experience challenges because of COVID-19 (OR=2.12, p=0.0496), were less uncomfortable with telehealth (OR=0.034, p=0.0350), had increased anxiety and stress, and experienced less distress due to COVID19 (OR=0.47, p=0.0490) compared to female participants. Conclusions: Challenges reported during the COVID-19 pandemic varied across sociodemographic groups, with elderly, male and black reporting the worst impact related to the pandemic. The vast majority of the survey participants reported increased stress, anxiety, or distress affecting quality of life and hindering access to care. The results of the study, however, suggest the important role of telehealth in addressing challenges and narrowing disparities in access to cancer care across the majority of participants.
Barriers and facilitators to implementing the Veterans Health Administration National Teleoncology Service: A qualitative descriptive study.
Authors: King Heather , Kelley Michael J. , Blue Colleen , Miller Julie , Raska Whitney , McWhirter Gina , Pura John A. , Jeffreys Amy , Zullig Leah L.
Published: June 2023

e13684

Background: Many Veterans lack local access to specialized cancer services. When timely VA care is not accessible, the VA covers the cost of care provided in a Veteran’s community. This benefit disrupts integrated care delivery within VA and may be less applicable for Veterans in areas where specialized cancer services may also not be available locally. The National TeleOncology (NTO) service was established to provide remotely delivered cancer services and increase access for Veterans to specialized cancer care. We sought to understand early implementation experiences as part of an ongoing evaluation of the VA National TeleOncology (NTO) service. Methods: Informed by the Consolidated Framework for Implementation Research (CFIR), we conducted a qualitative descriptive study using virtual individual interviews with Veterans (results not reported) and focus groups with clinicians. To identify and describe implementation barriers and facilitators, oncologists, nurse practitioners (NPs), and registered nurses (RNs) who provide care via teleoncology were asked about the need for NTO, its advantages/disadvantages compared to alternatives, and how to operationalize and measure NTO’s success. Additionally, Veterans who have participated in the teleoncology program were asked about their experiences; the analysis of this data is ongoing. We employed a team-based, rapid qualitative analysis using structured forms for notetaking. Theme matrix techniques facilitated data analysis and presentation. Findings were mapped to CFIR domains and constructs. Results: Guided by information power, we conducted 15 individual interviews with Veterans and three focus groups, separated by clinician type. The individual interviews lasted approximately 36 minutes, and focus groups lasted approximately 30 minutes. Most Veteran participants were male (87%), white (60%), and had prostate cancer (47%). Results from our analysis suggest that clinicians feel there are key challenges/barriers to engaging NTO: 1) can delay care; 2) perception that NTO may not be as personable as in-person care; 3) technology access/use can be difficult for some Veterans. They also reported key advantages/facilitators: 1) provides Veterans nationwide with accessibility to cancer specialists; 2) keeps patients in VA system to support better care coordination and team-based care that expedites needed follow-up services. Conclusions: Those involved in implementing NTO feel supported and that it works well overall, especially to provide better coordinated cancer care for Veterans. These data will support an ongoing NTO evaluation. Separate data collection efforts are underway to understand the quality of care delivered to inform the widespread scale-out and delivery of NTO.
Relationship between efficacy of phase I/II drug ispinesib in medulloblastoma, molecular subtypes, and p53-mutant status.
Authors: Teo Wan-Yee , Huang Shiying , Du Yuchen , Major Angela , Su Jack M. , Hui Kam Man , Elghetany M. Tarek , Li Xiao-Nan
Published: June 2023

e14001

Background: KIF11, a mitotic kinesin, is responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11 to enhance tumor proliferation. Many cancers overexpress KIF11, including medulloblastoma (MB), the most common malignant brain tumor in children. MB is molecularly classified into 4 molecular subtypes: sonic-hedgehog (SHH)-activated MB, Wingless (WNT)-activated, and less characterized Group 3 and 4 subtypes. Group 3 and 4 MBs are the most aggressive subtypes and Group 3 MBs have the worst survival outcome. p53 mutation defines a high-risk group in MB patients. We evaluated the efficacy of a Phase I/II KIF11 inhibitor, ispinesib on MB. Methods: We employed in-vitro proliferation assays (CCK), flow cytometry (Annexin V, Propidium Iodide), western blot, Hoechst staining, and two patient-derived orthotopic xenograft (PDOX) mouse models for in-vivo drug testing. Results: Ispinesib effectively inhibited proliferation at nanomolar concentrations for all 5 MB cell lines. A comparison of IC50 (day 4) indicated that p53-mutational-status did not influence sensitivity to ispinesib. In all five cell lines, regardless of p53 mutational status, ispinesib led to G2/M arrest. However, different p53-mutational-status led to different modes of cell death. High levels of necrotic cell death were observed in p53-mutant, while apoptosis was the predominant mode of cell death in p53-wildtype, on flow cytometry. Apoptotic nuclei were more significantly observed in p53-wildtype (p = 0.002) while p53-mutant cell line demonstrated more micronuclei (p = 0.0302) and multi-nucleation (p= 0.0161), compared to respective DMSO-control cells on Hoechst staining. Ispinesib has demonstrated effective blood brain barrier penetration in brain xenografts. We compared 2 PDOX models of MB. Ispinesib significantly improved survival outcome of Group 3 MB (Control=6, Treated=7, Log-rank p=0.0003), but worsened the survival outcome of p53-mutant SHH MB (Control=14, Treated=11, Log-rank p=0.169). This differential efficacy of ispinesib was recapitulated in the matched 3D-neurosphere cultures of both PDOX models. Cancer-stem-cell (CSC)-enriched neurospheres derived from aggressive Group 3 subtype demonstrated susceptibility to 7-day in-vitro treatment with ispinesib (AUC=0.7743). Monolayer tumor cells demonstrated similar susceptibility (AUC=0.7757). Area under curve (AUC)>0.7 was the significant cut-off. In contrast, both CSC-enriched neurospheres (AUC=0.379) and monolayer tumor cells (AUC=0.491) derived from p53-mutant SHH MB did not demonstrate susceptibility to ispinesib, consistent with matching PDOX models. Conclusions: Preclinically, our results indicate feasibility of ispinesib treatment in MB, specifically aggressive Group 3 MB. Importantly, p53-mutant SHH MB represents a poor molecular-subtype candidate for ispinesib therapy.
Outcomes with bevacizumab for radiation induced-brain necrosis.
Authors: Muminovic Meri , Uribe Carlos Carracedo , Dalal Shivani , Castellon Ignacio , Falchook Aaron , Nano Olger , Raez Luis E.
Published: June 2023

e14006

Background: Radiation necrosis (RN) is post-radiation complication that leads to increased permeability and disruption of the blood brain barrier (BBB). This in turn leads to a pro-inflammatory state and an increased production of vascular-endothelial growth factor (VEGF). Bevacizumab is a monoclonal antibody against VEGF and is a potential treatment for RN. The objective of the study is to assess effectiveness of bevacizumab (BEV) for the treatment of brain RN in adults. Methods: Retrospective chart review of 22 patients with various solid malignancies including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), metastatic melanoma and breast cancer with clinical or radiographic diagnosis of RN seen at Memorial Cancer Institute (MCI) in a 3-year period, from January 1st, 2019 to January 1st, 2023. Radiation doses ranged from 18-24 Gy (single fraction) or 24-27 Gy (3-fraction) for radiosurgery and 30-37.5 Gy for whole brain radiotherapy. Patients were identified that developed RN and VEGF inhibitors were subsequently given to assess effectiveness in the treatment of the condition. We evaluated the dose, frequency, number of treatments received, adverse effects and therapeutic benefits of BEV. Therapeutic benefit was defined as patients that received bevacizumab had a radiological and clinical improvement of the RN (clinical benefit). Brain imaging with MRI or PET/CT scan was completed both pre and post treatment to evaluate efficacy of treatment. Patients were initially given 4 cycles with a subsequent 4 more cycles if it was beneficial and tolerated treatment. Results: 22 patients were included in the study, 9 were males (41%) and median age 66 (range 31-81). 91% (20/22) had a diagnosis of lung cancer. 1 patient had a diagnosis of SCLC, while 19 were diagnosed with NSCLC. The study had a good representation of different races including Non-Hispanic Whites 7 (32%), Hispanics 10 (45%), Blacks 13% (3) and Asians 10% (2). Over 95% (21/22) of patients achieved a clinical benefit, while one patient did not (5%). Patients experienced improvement in cognitive function, headaches, dizziness, weakness, and other symptoms with BEV. MRIs showed improvement in edema and a reduction/stabilization of brain lesions. The most frequent dosing regimen used was BEV 10 mg/kg every two weeks. The median number of cycles given was 4 cycles (1-12). The most common adverse events were hypertension, minor nose bleeding, an occasional protein found in urine. There were no severe AEs or discontinuation of therapy with bevacizumab. Conclusions: This study demonstrated treatment with BEV 10 mg/kg every two weeks for a total of 12 cycles is well tolerated and has potential clinical benefit in RN in lung cancer patients with CNS metastasis. The therapeutic effects of VEGF inhibitors were seen in our small population study but warrants further investigation in a larger population study.
A characteristic comparison of cell-free DNA isolated from plasma and cerebrospinal fluid in patients with cancer.
Authors: Zhang Jian , Wang Wei , Li Yingmei
Published: June 2023

e14008

Background: Cell-free DNA (cfDNA) from plasma has proved its power as a liquid biopsy analyte in many cancer types, except cancers from central nervous system (CNS). CfDNA from cerebrospinal fluid (CSF) better recapitulates mutations for primary CNS tumors or cancer brain metastasis. The characteristics of cfDNA from plasma, including concentration range, mutation frequency, length, end motif etc. have been thoroughly studied, while the features of cfDNA from CSF are yet to be investigated. Methods: We retrospectively reviewed records since 2021 from a clinical sequencing center, and selected samples from patients with non-small cell lung cancer. CfDNA from 30 CSF and 85 plasma samples was isolated, followed by NGS library preparation procedures, and enriched with a 680-gene panel. Fragmentation features including cfDNA length distribution and frequency of 6-bp end motif sequences were analyzed after removal of UMI. K-means clustering algorithm was utilized to analyze fragment motifs. Results: The mean concentration of cfDNA isolated from plasma and CSF was 13.46 ng/mL (1.28 – 96.40, 95%) and 26.82 ng/mL (2.80-382.00, 95%) respectively. A larger proportion of longer cfDNA fragments (>200bp) in CSF sample was observed, 37.8% in CSF VS 22.8% in plasma. Several end motifs were identified to be highly enriched in either sample type, and we found that sample types could be separated by K-means clustering from top 10 motifs. Conclusions: CSF is a less complicated solution system than plasma, regarding chemical constitutes. The cfDNA length distribution and motif patters are distinguishable in CSF and plasma. Our analysis demonstrated that the characteristics of cfDNA in CSF are obviously different from cfDNA in plasma, and the underlying mechanism remains to be clarified.
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]
Mutational profiling of newly diagnosed glioblastoma to identify predictive biomarkers of efficacy and safety of anlotinib combination therapy.
Authors: Lai Shuzhen , Li Peijing , Liu Xiaohui , Liu Guihong , Xie Tieming , Zhang Xing , Wang Xiaoxuan , Huang Jing , Tang Yiqiang , Liu Zhigang , Shen Guoping , Li Chaoming , Lu Fangxiao , Wang Lei , Jiang Fagui , Sun Caixing , Chen Yuan yuan Yuan
Published: June 2023

e14037

Background: Glioblastoma (GBM) is highly vascular tumor with the specific pathologic feature of microvascular proliferation. Our previous phase Ⅱ clinical trial (NCT04119674) has firstly demonstrated the antiangiogenic multikinase inhibitor anlotinib combined with STUPP regimen can lengthen progression-free survival (PFS) in patients with newly diagnosed GBM. However, no biomarker for angiogenic therapy has been proved yet. Therefore, the second analysis was performed to identify the predictive biomarkers. Methods: A total of 21 patients with newly diagnosed GBM were enrolled in the retrospective research. The methylation status of the MGMT gene promoter was examined using the MDxHealth PCR assay. DNA-based whole genome sequencing was undertaken to detect the genomic alterations of patients. Results: The differences of gene aberrances between patients who reached and those who did not reach the primary endpoint were observed. ATRX and MYO15A mutations were only found in patients who had yet not experienced relapse. On contrast, the mutations of PIK3CA, HEG1, HMCN1 and RP1L1 occurred only in the recurrent group. HEG1 (HR 6.0, 95% CI 1.2-28.8, p= 0.026) and RP1L1 (HR 12.5, 95% CI 2.1-74.3, p= 0.005), genes related to angiogenesis, were both independent biomarkers of PFS. RP1L1 was also significantly associated with shorter overall survival (OS) (HR 33.4, 95% CI 3.2-351.4, p= 0.003). Interestingly, PIK3CA alterations were significantly higher in patients with cerebral than in those without ( p= 0.032, OR 16.4). Conclusions: Our study suggested that alterations in HEG1, RP1L1 and PIK3CA could be novel biomarkers for the newly diagnosed GBM patients received anti-angiogenesis combination therapy, and provided now insights for the precise treatment of GBM.
Modulating MDSCs by HF1K16: A mono-therapy phase Ia study examining safety and preliminary efficacy in patients with refractory and metastatic cancer.
Authors: Xu Yuhong , Zheng Anjie , Huang Ruofan , Liu Jian , Zhang Xiaochen , Chen Jian , Fang Hongming , Dai Yongchao , Liu Jianming , Jin Shanshan , Wu Xuan , Wang Xun , Guo Wenjun , Huang Yongfeng , Wu Jinsong
Published: June 2023

e14040

Background: Immature myeloid cells or the so called Myeloid-derived suppressor cells (MDSCs) are found to be present in higher numbers in cancer patients' PBMCs and in tumor infiltrating cells. All-trans retinoic acid (ATRA) is a natural vitamin A metabolite that's capable of inducing MDSC maturation and differentiation at uM concentrations. HF1K16 is an ATRA liposome formulation developed by Hangzhou Highfield Biopharm that aims to deliver ATRA to the tumor microenvironment by i.v. infusion for MDSC mediated immuno-therapeutic effects. Methods: The HF1K16 phase Ia clinical trial (NCT05388487) is being conducted to study the tolerability and safety of HF1K16 in patients with refractory solid tumors based on a "3+3" dose escalation scheme. HF1K16 infusions were given every other day for 2 weeks followed by a break week, and the 3wk cycle were repeated until EOT. Safety and tolerability records, repeated dose PK parameters, as well as exploratory PD analysis of PBMC samples are evaluated during the first cycle of treatment. Efficacy evaluations are followed every 6 weeks or less until EOT. Results: As of January 30, 2023, there have been 11 patients enrolled into the study in the dose groups of 45 mg/m2, 90mg/m2 and 120 mg/m2. The patient diagnosis and up to date treatment information is shown. Clinical trial information: NCT05388487 . Conclusions: HF1K16 is well tolerated at the 45 mg/m2 and 90 mg/m2 dose levels when given as monotherapy. Using the RECIST 1.1 criteria, one patient achieved an objective response with a progressive reduction of the target lesion from 70mm to 23.7mm. Four patients had PFS longer than 3 months. There is a subgroup of five enrolled patients who have recurrent and refractory Glioblastoma with multiple prior treatments. Three of them had control of disease and are still under treatment. The study is also still on going. We will collect more data based on additional enrolled cases and plan for the next phase study of HF1K16. [Table: see text]
Incidence of thromboembolic events in glioblastoma multiforme: The first Middle Eastern study risk stratifying patients from this region.
Authors: Hassan Mona , Finianos Antoine Nafez , El Hasbani Georges
Published: June 2023

e14044

Background: Prophylactic anticoagulation for Glioblastoma Multiforme patients remains an area of high controversy with no definite guidelines and with clinical practice recommendations depending mainly on individual center based strategies. Considering that the middle eastern population is known to be associated with increased incidence of thrombophilia due to the high prevalence of factor V R506Q Mutation-Leiden and with no studies reporting incidence of VTE with GBM patients in this region, we aimed to conduct the first middle east based study to see if the incidence of VTE in GBM patient will be higher than the other overall reported incidence worldwide and we looked whether using the Khorana score will be a good predictor for assessing the need for VTE prophylaxis in these patients. Methods: we conducted a retrospective chart review to determine the incidence of initial VTE in GBM patients who received treatment at a tertiary care center in Beirut. Results: The total patient population was 132 with males constituting 71.2% of our population compared to 28.8 % females. Preexisting risk factors included: 34.8 % for hypertension, 65.2% for diabetes, and 25% were smokers, 0.8% had history of thrombophilia, and 7.6% had preexisting episode of VTE while 94% of the population had craniotomy. The incidence of deep vein thrombosis (DVT) was 15.4%, while 7.2 % developed a pulmonary embolism (PE). Recurrent VTEs affected 34.8% of those who had a previous VTE, and 7.4% of patients had the recurrent VTE while they were on anticoagulation. Regarding complications, 7.3% developed bleeding, 66% of those had intracranial bleeding while 33 % had a gastrointestinal bleed. Out of all of those who developed bleeding, only 3.4% were on anticoagulation so anticoagulation was not a major risk factor for bleeding. 57.6% of the patients had a Khorana score of 0, 28.8% had a score of 1,7.6% had a score of 2,1.6% had a score of 3, while 8% had a Khorana score of 4. In our cohort, all patients with a Khorana score of 3 and 4 developed VTE which indicated that this could be used as a risk assessment tool for our GBM patients. Conclusions: In conclusion in our study, with its retrospective limitation, we could not prove that our middle eastern populations, though known to have higher incidence of congenital thrombophilia, is associated with much higher incidence of VTE when compared to many studies involving different populations in the world however our cohort of patients with GBM undergoing craniotomy are still at increased risk of thrombotic events with low risk of bleeding despite anticoagulation and the Khorana score could be a risk stratifying method to help us establish the patients who have the highest risk of developing VTE. Prospective studies involving higher number of patients with thrombophilia testing should be explored to risk stratify our patients.
PIK3CB as a potential target to regulate chemosensitivity in glioblastoma.
Authors: Beck Patrick , Hutchings Kasen Reed , Xu Eileen , McDaid Erin , Bui Vincent , Patel Chinkal , Solis Jaime , Huang Leah , Tegge Allison , Kelly Deborah F , Sheng Zhi
Published: June 2023

e14051

Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy but exhibits universally poor outcomes in part due to chemoresistance. Temozolomide (TMZ) can significantly improve overall survival, but resistance mechanisms limit its consistent efficacy. The phosphoinositide 3 kinase (PI3K) pathway is involved in multiple TMZ resistance mechanisms and is highly druggable; however, pan-inhibition of its four grossly homologous but functionally distinct catalytic subunits (PIK3CA/B/D/G encode p110α/β/δ/γ, respectively) was unsuccessful clinically. Therefore, by understanding how the individual PI3K subunits regulate TMZ sensitivity, a more selective treatment strategy can be developed to combat chemoresistance. Methods: Differential expression of PI3K subunit genes was assessed using RNA sequencing (RNAseq) results obtained from public databases (e.g., DepMap, The Cancer Tissue Genome Atlas) for GBM cell lines and patient tumors expressing high or low O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair enzyme highly implicated in TMZ resistance. PI3K protein levels were assessed using immunohistochemistry of gliomas available at The Human Protein Atlas (THPA). PI3K gene expression was correlated with PI3K pathway activation, quantified as protein kinase B phosphorylation (pAKT). PI3K mRNAs and pAKT were then correlated with the half maximal inhibitory concentrations (IC50s) of TMZ in GBM cell lines to evaluate for a relationship between PI3K gene expression, PI3K pathway activity, and TMZ sensitivity. Finally, hazard ratios were used to compare PI3K gene expression in patient tumors with survival and response to chemotherapy to determine if expression was predictive of prognosis and/or chemosensitivity. Results: PIK3CB was the only PI3K gene enriched in both GBM cell lines and tumors, demonstrating significantly higher expression than all other PI3K genes in GBM (P < 0.0001), independent of MGMT levels. PIK3CB expression remained the highest even after controlling for GBM risk factors such as tumor recurrence, isocitrate dehydrogenase (IDH) mutations, molecular subtypes, or patient gender/age differences. Levels of the p110β protein were also significantly higher than those of other PI3K catalytic subunits (P < 0.001). PIK3CB expression was positively correlated with pAKT levels (P < 0.05), but only in cell lines and tumors with low MGMT activity. Both PIK3CB expression and pAKT levels correlated positively with TMZ IC50s (P < 0.05) in MGMT-deficient GBMs, suggesting an inverse relationship between PIK3CB and TMZ sensitivity. Finally, better prognosis and significant survival benefit with chemotherapy were both associated with lower levels of PIK3CB in MGMT-deficient patients. Conclusions: PIK3CB may selectively regulate chemoresistance in GBM, suggesting a role for p110β selective inhibition to improve chemosensitivity.