bluuebunny/crossref_metadata_2025_split huggingface dataset:
The epidemiology and current treatment of pediatric choroid plexus carcinoma: An analysis of the national cancer database.
Authors: Wu Xinxin , Swedek Michelle , Griffin Julia , Malouff Timothy Dean , Silberstein Peter T. 
Published: June 2022

e14024 Background: Choroid Plexus Carcinoma (CPC), a subtype of choroid plexus tumors (CPT), is a rare central nervous system neoplasm mostly affecting the pediatric population. The epidemiology of CPC is poorly understood due to the rarity of the disease. By analyzing the National Cancer Database (NCDB), we describe the demographic and social factors that influence the risk and current treatment of the cancer. Methods: We conducted a retrospective cohort analysis utilizing the 2018 National Cancer Database (NCDB) and included patients with Choroid Plexus Carcinoma with a histology-confirmed WHO grade III tumor, between ages 0-99 years (N = 202). Analysis was completed for the frequency of cases, types of treatment received, and overall survival within the pediatric population (age < 18 years, N = 139) and the adult population. Demographic factors were analyzed using Pearson Chi-squared tests, and survival was estimated using Kaplan-Meier curves. Results: The majority of the cases analyzed were white (55.4%), male (54%), and pediatric patients (66.8%, mean age at diagnosis = 15.17 years) with an average Charlson-Deyo Score of 0.24. The mean age at diagnosis of the pediatric population was 2.34 years (min = less than 1 years old/diagnosed in utero, max = 16, std. deviation = 3.84) while the mean age at diagnosis of the adult population was 43.49 years (min = 18, max = 84, std. deviation = 18.23.) The most common primary site for CPC was malignant neoplasm of the cerebral ventricle (87.6%) followed by malignant neoplasm of the brain stem (5.9%). Surgical procedure of the primary site was performed in 92.6% of cases including local excision, subtotal resection, resection, radical resection, partial resection of a lobe of brain, lobectomy, and surgery NOS. Radiation was not used 71.3% of the time, but was more than three times as likely to be used in the adult population after surgery than in the pediatric population after surgery (44.4% vs 14.4%, p value < 0.001). Most patients received chemotherapy (53%) with the administration of chemotherapy higher in the cohort less than 18 years old (69.8% versus 15.9%, p value < 0.001). Multiagent chemotherapy was administered as the first course of therapy as the top chemotherapeutic choice (86%) especially among the pediatric population (88.6%) compared to the adult population (60%) Palliative care was not provided in any of the cases. There was no statistical significance difference between the general survival of CPC between the pediatric and adult population. Conclusions: Historically, CPC is known as a pediatric cancer, but this NCDB study suggests that the frequency of the adult population affected is not negligible (31.2%). There is a difference regarding the current treatment of CPC in the pediatric versus adult population. Further study is needed to determine the impact of treatment and the importance of socioeconomic factors on the survival of CPC.
A novel glioblastoma prognostic assay using droplet digital polymerase chain reaction.
Authors: Beck Patrick , Hutchings Kasen Reed , Grant Caroline , Sheng Kevin , Morales Joshua Aaron , Varghese Robin , Sheng Zhi 
Published: June 2022

e14026 Background: Glioblastoma (GBM) is an incurable brain tumor for which outcomes have seen little improvement in the past 30 years. Despite limited GBM therapies, accurate prognostic tools can be invaluable in informing best course of treatment. Recently, we have identified the GBM progression gene signature (GBM-PGS), a collection of 31 genes that shows superior accuracy at predicting GBM progression compared to existing biomarkers. From GBM-PGS expression, a GBM progression risk score can be calculated to provide clinicians with patient-tailored prognostic information. However, the question remains as to the best way to measure GBM-PGS to create a clinically applicable test. At our disposal are three approaches to quantify gene expression: quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), and RNA sequencing (RNA seq). We hypothesize that the combination of high accuracy and sensitivity, while also providing absolute quantification, will deliver ddPCR as the best option for creating a rapid clinical test that is scalable for measuring GBM-PGS. Methods: A ddPCR protocol was developed, and cDNA and primer concentrations were optimized using samples from two GBM cell lines (SF295, LN18). To confirm assay accuracy, GBM-PGS was quantified using ddPCR and compared to GBM-PGS expression by qPCR, a protocol that has previously been thoroughly validated. Finally, GBM-PGS expression was measured in patient tumors using ddPCR, and the GBM-PGS risk score algorithm was trained using an RNA seq data set from the Tissue Cancer Genome Atlas (TCGA). Following training, risk scores were calculated for the patient samples using ddPCR-measured GBM-PGS expression. Risk scores were compared with clinical patient survival to determine if GBM-PGS expression measured by ddPCR could predict patient outcomes. Results: Optimal primer concentration (200 nM) and cDNA concentration (1.2 ng/μl) were identified. GBM-PGS expression measured by ddPCR absolute quantification and qPCR Ct value demonstrated a strong correlation in the SF295 (R2 = 0.91) and LN18 (R2 = 0.88) cell lines. GBM-PGS was measured in two patient samples, and the resulting risk scores were calculated as 26.6 and 29.8 (score > 0 = high progression risk; score < 0 = low progression risk) compared to disease free survival times of 12.9 and 10.5 months, respectively, demonstrating an inverse relationship between patient risk score and survival time. Conclusions: Our results demonstrate that we have developed an accurate ddPCR-based assay capable of measuring GBM-PGS in multiple GBM cell lines, and preliminary results suggest that GBM-PGS quantified using ddPCR accurately predicts patient survival.
The landscape of EGFR mutation in Chinese patients with glioma.
Authors: Zhang Hui , Tao Rongjie , Zhu Xiaofeng , Luo Ningning , Qi Yingxue , Li Mengmeng , Sun Tingting , Qi Chuang 
Published: June 2022

e14028 Background: Epidermal growth factor receptor (EGFR), a trans-membrane receptor tyrosine kinase, consists of an extracellular ligand-binding domain (ECD), a single transmembrane domain (STMD) and an intracellular kinase domain (ICD). Glioma is the most common primary brain tumor, and variations of EGFR are frequently reported in glioma patients. This study aimed to analysis the landscape of EGFR mutation subtype in Chinese patients with glioma. Methods: We retrospectively collected 1779 patients with glioma. In all patients enrolled, the comprehensive genomic profiling containing EGFR gene was detected using tumor tissue, including WES, 539 tumor related-gene panel or 131+4 gene panel (Simceredx). And the somatic mutations including SNV, INDEL, CNV, fusion were analyzed correspondingly. Results: Among 1779 patients with glioma, EGFR mutations were identified in 392 (22.03%) patients. The age was significantly higher in patients with EGFR-mutant group than in patients without EGFR-mutant group, with median age 54 vs. 45 (p = 4.81e-19). The sex didn’t reach statistical significance in two group. The incidence rate of different EGFR mutation types among all patients with EGFR-mutant were amplification (314,80.10%), SNV(198,50.51%), Indel(24,6.12%) and fusion(44,11.22%) respectively. 162 (46.69%) had two or more mutation types simultaneously. The main partner gene of EGFR fusion was LOC100996654, followed by ELDR and SEC61G, and the main EGFR breakpoints were in intron24, intron7, exon7. Within 347 SNV and Indel mutations, exon7, 15, 20, 6 and 8 were detected in 103(29.68%), 50(14.41%), 28 (8.07%), 25(7.20%) and 18 (5.19%) respectively. The top three mutaton subtypes within exon7 were account for 19.31%, which included p.A289V,p.A289T,p.T263P. Meanwhile, the mutation frequency within ICD encoded by exons 18-24 was 17.00%, in which exon20 mostly distributed (8%). In exon20, the most common mutation subtypes were p.V774M,p.H773dup,p.T790M, while in the second proportion exon18 (3.46%), the main subtype were p.G719A/D. Conclusions: EGFR amplification was the most common mutation type. There were 122 SNV and Indel subtypes altogether and occurred throughout almost the entire exon region, in which exon7 contained maximum 21 different subtypes and the p.A289V was the main type. The distribution of subtypes in ECD were much more than in ICD. The relationship between subtypes occurrence and cancer will be further studied in the future.
Retrospective review of glioma patients with confirmed MET amplification or fusion.
Authors: Tadipatri Ramya , Miller Adela , Ekhator Chukwuyem , Ahluwalia Manmeet Singh , Grewal Jai , Fonkem Ekokobe 
Published: June 2022

e14029 Background: The MET pathway is a key oncogenic pathway in gliomas and is involved in tumor survival, angiogenesis, and invasion. MET alterations have been increasingly identified as a potential therapeutic target. Methods: Our objective was to further characterize the natural history of gliomas which harbor MET alterations and study outcomes as determined by progression free survival (PFS) and overall survival (OS). Results: We identified 22 glioma patients seen at our institution between 2015 and 2021 who had a MET alteration confirmed through comprehensive molecular profiling. There were 18 grade 4 astrocytomas/glioblastomas, 3 grade 3 gliomas (2 astrocytomas, 1 oligodendroglioma), and 1 grade 2 glioma (oligodendroglioma). MET amplification was observed in 13 patients and fusion in 16 patients, with 7 patients carrying both amplification and fusion alterations. MET fusion partners included PTPRZ1 (8 patients), CAPZA2 (6 patients), and ST7 (3 patients). Median OS was 12.8 months, and median PFS was 8.47 months. IDH1/2 mutation was associated with significantly improved survival, with an estimated OS of 146 months for IDH1/2 mutant tumors and 17.9 months for IDH1/2 wildtype tumors (F2,2 = 38.907, p < 0.001), MGMT methylation status had no significant survival impact. No significant survival differences were observed between the fusion only, amplification only, and combined fusion and amplification groups. No therapy was predictive of improved outcomes. Conclusions: MET amplification and fusion alterations were observed in both low and high grade gliomas, suggesting that they may be involved in early tumorigenesis. Survival outcomes were poor compared with historical data, with no differences observed between treatment groups, suggesting that current therapeutic modalities may be inadequate. This study indicates that MET may be an appropriate therapeutic target, laying the groundwork for clinical trials investigating MET-targeted agents.
Genomic features of IDH-mutant adult diffuse astrocytoma.
Authors: Zhang Hongjun , Duan Qianqian , Zhang Qin , Tan Yuan , Sun Tingting , Qi Chuang 
Published: June 2022

e14032 Background: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, which indicated that all IDH mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH-mutant) and are then graded as CNS WHO grade 2, 3, or 4. Besides, the guideline eliminates the term “Glioblastoma (GBM), IDH-mutant”. Moreover, grading is no longer entirely histological, since the presence of CDKN2A/B homozygous deletion results in a CNS WHO grade of 4, even in the absence of microvascular proliferation or necrosis. Therefore, more clinical and genomic characteristics of IDH-mutant astrocytoma under molecular typing need to be further studied. Methods: Adults pathological diagnosed with diffuse astrocytoma and glioblastoma in our Chinese dataset were identified retrospectively. All patients included in the analysis were tested for 131 CNS tumor-related genes (including IDH1/2), chromosomes 1p/19q and chromosomes 7/10. Results: 63 initial diagnosed IDH-mutant diffuse astrocytomas including 46 patients with grade 2-3 and 17 patients with uncertain grade. While, 5.2% of GBM (9/174) harbored IDH1/2 mutation which should be redefined as diffuse astrocytoma, IDH-mutant, WHO 4 grade. And these patients had a high frequency of CDKN2A/B homozygous deletion (88.9%, 8/9). In patients with 2-3 grade and unclear grade, CDKN2A/B homozygous deletion accounted for 18.7% (9/48) and 27.8% (5/18), respectively, which meant the grade of these diffuse astrocytomas should be revised to WHO 4 grade according to guideline. While mutation frequency of crucial prognosis factors in glioma, including chromosomes 7 loss, chromosomes 10 gain, EGFR amplification, PIK3CA/R1, PDGFRA amplification, CDK4 amplification, were 9.7%, 2.8%, 5.6%, 13.9%, 6.9% and 8.3% in all 72 astrocytomas, respectively. In addition, we found 83.3% (5/6) KDR copy number variant were occurred in which initially pathological diagnosed as IDH-mutant GBM. Conclusions: we conducted comprehensive analysis of IDH mutant diffuse astrocytoma. CDKN2A/B homozygous deletion as a specific grade-classified molecular marker could better re-distinguish about 20%-30% 2-3 grade and uncertain grade astrocytoma. KDR copy number variant may be a marker in IDH-mutant astrocytoma to identify the tumor which pathology is closer to GBM.
Toxicity of concurrent and adjuvant temozolomide in patients with glioblastoma multiforme (GBM).
Authors: Mcmahon David , Hussein Awab , Mangleburg Hunter , Nichianain Aine , Fitzpatrick Orla , McLaughlin Ronan Andrew , Conroy Michael R. , Marks Sam Jonathan , Naidoo Jarushka , Grogan William , Murphy Adrian Gerard , Breathnach Oscar S. , Hennessy Bryan T. , Morris Patrick G. 
Published: June 2022

e14037 Background: (MGMT) promotor is prognostic and predictive of temozolomide (TMZ) benefit in newly diagnosed GBM. It has been suggested that MGMT methylation is associated with TMZ toxicity in some cancers such as melanoma but is not clearly defined in GBM. Methods: To investigate this, a retrospective electronic chart review of patients (pts) with resected GBM in a tertiary neurosurgical referral center from 1 July 2017 – 31 Dec 2020 was conducted. Hematological toxicities during TMZ with RT (concurrent) and subsequent TMZ (adjuvant) were assessed and graded by CTCAE V5.0. Toxicity was compared by MGMT methylation status. Results: In a 3.5 year period, 417 GBM resections were performed. Of these, 186 (45%) patients received at least 1 dose of TMZ in our institution: 180 pts received concurrent TMZ, 6 pts received adjuvant only. MGMT was methylated, unmethylated and unknown in 72, 97 and 17 pts respectively. In the concurrent and adjuvant phases respectively, thrombocytopenia incidence was 20%(N=14) and 52%(N=25) in the methylated group and 15%(N=15) and 51%(N=37) in the unmethylated group. In the adjuvant phase, incidence of ≥ grade 3 thrombocytopenia was 8%(N=4), in the methylated patients and 9%(N=7) for those unmethylated. Neutropenia incidence was low in the concurrent phase, however in the adjuvant phase was 29%(N=14) in the methylated group and 23%(N=17) in the unmethylated group. ≥G3 incidence was 10%(N=5) and 3%(N=2) respectively. Conclusions: In this retrospective study, a higher incidence of hematological toxicity was not seen in pts with MGMT methylated tumors. Methylation of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase.[Table: see text]
A prognostic model for overall survival in primary central nervous system lymphoma using post-steroid neutrophil-lymphocyte ratio.
Authors: Lo Yu Tung , Lim Vivian Yujing , Ng Melissa , Tan Ya Hwee , Chiang Jianbang , Chang Esther Wei Yin , Chan Jason , Poon Eileen Yi Ling , Somasundaram Nagavalli , Harunal Rashid Mohamad Farid Rin , Tao Miriam , Thye Lim Soon , Yang Valerie Shiwen 
Published: June 2022

e14049 Background: Ratios of differential blood counts (hematological indices, HI) had been identified as prognostic variables in various cancers. In primary central nervous system lymphomas (PCNSL), higher baseline neutrophil-lymphocyte ratio (NLR) in particular was found to portend a worse overall survival. However, it was often observed that differential counts shift drastically following steroid administration. Moreover, steroids are an important part of the arsenal against PCNSL due to its potent lymphotoxic effects. We showed that the effect of steroids on differential blood cell counts and HI could be an early biomarker for subsequent progression-free (PFS) and overall survival (OS). Methods: This study retrospectively identified all adult patients who received a brain biopsy from 2008 to 2019 and had histologically confirmed PCNSL, and included only those who received chemoimmunotherapy, with documented use of corticosteroids prior to treatment induction. Different blood cell counts and HI were calculated at three time-points: baseline (pre-steroid), pre-chemoimmunotherapy (post-steroid) and post-chemoimmunotherapy. Tumor progression and survival data were collected and analyzed through Kaplan-Meier estimates and Cox regression. We then utilized selected variables found to be significant on Kaplan-Meier analysis to generate a decision-tree prognostic model, the NNI-NCCS score. Results: A total of 75 patients who received chemoimmunotherapy were included in the final analysis. For NLR, OS was longer with higher pre-chemoimmunotherapy (post-steroid) NLR (dichotomized at NLR≥4.0, HR 0.42, 95% CI: 0.21-0.83, p = 0.01) only. For platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), OS was better for lower post-chemoimmunotherapy PLR (dichotomized at PLR≥241, HR 2.27, 95% CI: 1.00 to 5.18, p = 0.05) and lower pre-chemoimmunotherapy (post-steroid) LMR (dichotomized at LMR ≥25.7, HR 2.17, 95% CI: 1.10 to 4.31, p = 0.03) respectively only. Decision-tree model using age ≤70, post-steroid NLR > 4.0, and pre-steroid (baseline) NLR < 2.5 divided patients into three risk categories – low, medium, high – and achieved good accuracy (area-under-curve of 0.78), with good calibration (Brier score: 0.16) for predicting 2-year overall survival. Conclusions: We found that post-steroid NLR, when considered together with baseline NLR, has prognostic value, and incorporation into a prognostic model allowed accurate and well-calibrated stratification into three risk groups.
Clinical trial and translational research for cancer immunology in Asian countries: Understanding the new frontier.
Authors: Ordinario Mel Valerie Cruz , Kojima Yuki , Sudo Kazuki , Iida Namiko , Okamoto Shinichiro , Nakamura Kenichi , Yonemori Kan , Watanabe Keisuke , Imasa Marcelo Severino Bulauitan 
Published: June 2022

e14510 Background: Among the major advances in cancer treatment is the progress in cancer immunotherapy; however, despite the strides, there is few information specific to the Asian population. It is unclear to what extent clinical trial and translational research in cancer immunology are conducted in Asian institutions. Methods: This questionnaire-based survey was conducted among researchers and healthcare professionals who are involved in cancer immunology research and therapeutics in Asia-Pacific countries. The study identified the involvement of respondents in various phases of clinical trials, and immunotherapy research. In addition, the current capabilities of the institutions to conduct translational research were surveyed. Results: We received a total of 122 responses from 20 Asia-Pacific countries. More than half (58%) of the responders are currently conducting clinical trials on cancer immunology with 25% having performed more than 10 Phase 3 trials in the last 3 years. In clinical trials and clinical practice, immune checkpoint inhibitors were performed in most countries (81.8% and 88.6%, respectively). Clinical trials and clinical practice of CAR-T and TCR-T were performed only in some countries (CAR-T; 22.7% and 15.9%, TCR-T; 2.3% and 0%, respectively). In the absence of novel therapeutics in their institution, 18% of the responders refer their patient to facilities that have ongoing clinical trials. Among the institutions that perform Hematopoietic stem cell transplant (55.1%), the most common type offered include autologous (81.3%) and allogenic (70.8%) peripheral blood stem-cell transplantation. About 51.7% of the respondents have institutions that can conduct early drug phase development studies with only 11.2% capable of utilizing their own immunotherapeutic agents. Less than half of the respondents (40.7%) belong to institutions that have conducted translational researches using patient-derived samples for the last three years. Furthermore, more than half of the respondent institutions have no personnel that is experienced to handle and/or run patient-derived fresh peripheral blood or fresh tumors. Collaboration among neighboring countries can allow send out of specimens to other institutions that have such capability, however, 56.9% of countries have regulations or restrictions in transporting lymphocytes or tumor tissues. Conclusions: Oncologists and researchers in Asia recognize the importance of cancer immunology researches for patients. There were institutional and inter-country differences particularly in the conduct of early phase clinical drug development and translational research.
Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, Galectine-3 and NLRP3-MyD88-chemokine pathways.
Authors: Quagliariello Vincenzo , Passariello Margherita , Di Mauro Annabella , Cipullo Ciro , Paccone Andrea , Inno Alessandro , De Lorenzo Claudia , Maurea Nicola 
Published: June 2022

e14516 Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy for improving cancer therapy outcomes. However, several ICIs-induced side effects emerged in a fraction of these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. We studied the pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models. Methods: C57/Bl6 mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injections for 10 days. Before (T0) and after treatments (T10), analysis of fractional shortening, ejection fraction, radial and longitudinal strain were performed through 2D-echocardiography (Vevo 2100, Visual Sonics Fujfilm). Fibrosis, necrosis, hypertrophy and vascular/myocardial NF-kB expression were analyzed through Immunohistochemistry (IHC) of treated cardiac tissues. Systemic levels of SDF-1, myocardial expression of DAMPs (Fibronectin-EDA, S100/Calgranulin, Galectine-3), NLRP3, MyD88 and twelve cytokines/growth factors have been analyzed. In parallel, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines/growth factors were analyzed in the supernatant through colorimetric and enzymatic assays. Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Systemic SDF-1 was drastically increased after treatment with ICIs. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88. Conclusions: This study demonstrates that therapy with anti-CTLA-4 and anti-PD-1 antibodies increases systemic SDF-1 and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A significant secretion of pro-inflammatory cytokines in myocardial tissue was also induced after ICIs therapy. Significant histological changes were seen and strong vascular NF-kB expression was observed in all groups.