bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
Genomic analysis in NF2 meningiomas: Does co-mutation suggest new subgroups?
Authors: Xi Yanfeng , Guo Didi , Han Tiantian , Kong Rongrong , Chen Siqi , Ding Ran , Deng Wanglong , Bu Fanfeng , Cao Shangzhi 
Published: June 2023

e14058 Background: Meningiomas are the most common primary central nervous system tumours in the adults, accounting for approximately 30% of intracranial tumours. NF2 alterations are the most common genetic abnormality in meningiomas and are known to initiate events for aggressive-type meningiomas. The purpose of this study was to explore genomic characteristics of co-mutated genes in NF2 meningiomas. Methods: This study retrospectively analyzed the genomic alteration of 347 Chinese Meningioma patients during 2019-2022. Next-generation sequencing (NGS) was performed to detect gene mutations in tumor samples of the patients. Results: NF2 mutations were observed in 160 of 347 patients (46%). Our results showed the NF2-mutant patients tended to have older age compared with NF2-wildtype patients (average age: 56 vs. 47, p < 0.05), and meningiomas were more common in women in both groups. TERT promoter mutation or CDKN2A/B deletion occurred in 16/160 (10%) of all NF2-mutant meningiomas. The proportion of NF2 alterations in tumors that harbored CDKN2A/B deletion or TERT promoter mutation was similar to those without mutations (41.0% vs. 46.8%, χ2＝0.46, p > 0.05). 11 patients defined as NF2-mutant meningiomas were found to co-occurred with POLR2A (n = 3), TRAF7 (n = 3), PIK3CA (n = 2), PIK3R1 (n = 2), AKT1 (n = 1), SMO (n = 1), which were previously reported in a mutually exclusive pattern, identifying unique clinical cohorts. Surprisingly, we observed co-mutation in [ NF2 - TRAF7- PIK3CA] genes in a 43-year-old woman meningioma patient. Conclusions: In summary, NF2-mutant patients were observed in 46% Chinese meningioma population and tended to have older age. Interestingly, POLR2A, TRAF7, PIK3CA, PIK3R1, AKT1 and SMO mutations are reported as exclusive of NF2 mutations, were observed in 11 NF2-mutant patients in this study. The co-mutation of different driver genes in meningioma should be given enough attention, and their clinical significance remain further study.
Mutational landscape of intracranial germ cell tumors.
Authors: Wang Jiangong , Han Tiantian , Wang Mengjuan , Guo Didi , Kong Rongrong , Dong Yuwei , Ding Ran , Chen Siqi , Deng Wanglong , Bu Fanfeng 
Published: June 2023

e14060 Background: Intracranial germ cell tumours (GCTs) are relatively rare tumours of the central nervous system, which account for 1% to 3% of cases. The pathogenesis of intracranial GCTs is unknown, molecular diagnostic methods currently play only a minor role in the diagnosis of CNS germ cell tumours, which generally rest on histopathological and secretory features. The objective of this study was to explore the molecular profile associated with Chinese intracranial GCT patients. Methods: This study retrospectively analyzed the genomic features of 24 intracranial GCT patients. Next-generation sequencing (NGS) of 551-gene panel was performed to detect gene mutations in tumor and blood samples of the patients. Results: The tumors originated most frequently in the pineal region (41.6%, 10/24), followed by the sellar tumor (16.6%, 4/24). The average age of the patients was 14 years (range, 4-55years), There is a male preponderance of 2:1. The most common mutation genes were KIT (4.23%, n=6), KRAS (2.82%, n=4) and PTEN (2.11%, n=3). KIT mutations are mainly missense mutations concentrated in exon 17, exon 11 and exon 13. Exon 2 and exon 3 of KRAS gene were the main mutation hotspots, mainly G12X(2.08%) missense mutation. The co-mutation of KIT and KRAS was only in one patient. Unexpectedly, four patients (16.6%) carried germline deleterious mutations, in FANCA(n=1), FANCD2(n=1), FANCE(n=1), SDHA(n=1). Two of the patients with germline mutations co-mutated with KIT and KRAS, respectively. Conclusions: 16.6% of the intracranial GCT patients carry germline deleterious mutations, and 12.5% in Fanconi anemia (FA) gene. Overall, these findings indicate that the Fanconi anemia (FA) pathway and the PI3K/AKT pathway play a significant role in intracranial GCTs tumorigenesis.
Human epidermal growth factor receptor 2/3 (HER2/HER3) expression in higher-grade meningioma.
Authors: Mair Maximilian , Tomasich Erwin , Paiato Christina , Widhalm Georg , Eckert Franziska , Sahm Felix , Hainfellner Johannes A. , Berghoff Anna Sophie , Preusser Matthias 
Published: June 2023

e14063 Background: Meningiomas are the most frequently diagnosed primary central nervous system (CNS) tumors in adults. Although most meningiomas can be cured by resection, higher-grade lesions (CNS WHO grades 2 & 3) tend to recur, with limited systemic treatment options after exhaustion of local therapies. Antibody drug conjugates (ADCs) targeting human epidermal growth factor receptors 2 and 3 HER2/HER3) have shown remarkable clinical activity in solid tumors including breast cancer brain metastases and are under investigation in various malignancies. Methods: 64 patients with WHO grade 2 (atypical) and 3 (anaplastic) meningioma have been included. DNA methylation analysis has been performed using Illumina EPIC methylation arrays. Panel sequencing for NF2, PIK3CA, SMO, ARID1A, ARID1B, KLF4, SUFU, TERT promotor, and TRAF7 has been executed applying the Illumina NextSeq 500 platform. HER2 and HER3 expression was evaluated by immunohistochemical analysis using PATHWAY HER2 (4B5, Roche) and HER3 #12708 (Cell Signaling) antibodies on a Ventana Benchmark Ultra staining system. Results: In total, 44/64 (68.8%) patients with WHO grade 2 and 20/64 (31.2%) patients with WHO grade 3 meningioma were included. Median age at surgery was 60 years (range: 19-83), and 37/64 (57.8%) patients were female. DNA methylation classes according to the Molecular Neuropathology classifier were benign-1 in 10 (15.6%), benign-2 in 10 (15.6%), benign-3 in 4 (6.3%), intermediate-A in 26 (40.6%), intermediate-B in 4 (6.3%), and malignant in 10 (15.6%) out of 64 tumors. Weak membranous HER2 expression was observed in 1/64 (1.6%) tumor, which was categorized as WHO grade 3/intermediate-B meningioma characterized by infiltration of adjacent bone and fat tissue as well as positive Ki-67 staining of up to 39% of cells. Similarly, only one sample (1.6%) was HER3-positive which was diagnosed as WHO grade 2 tumor of methylation class benign-2, showing meningothelial morphology with elevated mitotic activity and a mutation in TRAF7. The single HER2+ as well as the HER3+ sample were from two distinct female patients. Conclusions: In our cohort, HER2 and HER3 were only infrequently expressed in a small subset of samples of different WHO grade, methylation class, and genetic background. Exploration of further targets of ADCs which are approved or under investigation in other tumors is currently ongoing.
Medullomyoblastoma: A study of demographic and socioeconomic factors.
Authors: Patel Sagar , Hsia Beau , Keirns Darby , Silberstein Peter T. , Wu Xinxin 
Published: June 2023

e14064 Background: Medullomyoblastoma is a rare cerebellar cancer theorized to be of teratomatous origin and a more aggressive variant of medulloblastoma primarily affecting children under 10 Despite treatment with excision surgery, the survival period is less than 1 year. There is no standard treatment and previous studies have only looked at median follow-up and radiotherapy. A study using National Cancer Database data would be beneficial to examine the impact of demographic factors on risk and treatment. Methods: A retrospective cohort study using data from the National Cancer Database from 2005 to 2019 analyzed 19 patients diagnosed with medullomyoblastoma. The study examined demographic factors such as age, sex, race, Hispanic origin, insurance coverage, distance from facility, and Charlson-Deyo score through descriptive statistics and evaluated trends in incidence through regression analysis. Results: A total of 19 patients were identified in the database with a confirmed diagnosis of medullomyoblastoma between 2005 – 2019, with a slightly declining incidence of patients diagnosed per year (R2 = 0.155). The average age of diagnosis was 13.5 years (SD = 12.5, range = 1 – 44 years), with 52.6% of affected individuals being children under the age of 10. Males and females were affected relatively equally (52.6% and 47.4%, respectively). The top primary site was the cerebellum (84.2%). Most individuals (94.7%) had Charlson-Deyo comorbidity scores of 0. The majority of individuals (68.4%) received treatment as some form of tumor excision surgery (local tumor excision with or without combination of photodynamic therapy, electrocautery, cryosurgery, wide excision, or radical excision). The majority of the patients were non-Hispanic and White (94.7%). A higher percentage of patients were privately insured (68.4%) than those who were uninsured or insured by Medicaid. The majority (84.2%) of patients lived in a metropolitan area. Patients lived an average of 48.6 miles (SD = 57.1, range = 0.6 – 189.5) from the treatment facility. No patients received palliative care. Conclusions: To the best of our knowledge, this is the first NCDB study on medullomyoblastoma, filling a crucial gap in knowledge. Results show the majority of patients are non-Hispanic White children, with primary site at the cerebellum, similar to previous case reports. For the first time, socioeconomic characteristics of medullomyoblastoma patients have been documented, such as the majority of patients being privately insured living in metropolitan areas. Treatment-wise, patients receive tumor excision surgery in the form of localized excisions or combination therapies. Currently, more attention is paid to pediatric cases, so a study on adult incidences would provide a more holistic assessment of the cancer. Further investigation is needed to understand the effect of demographic/socioeconomic factors on rarity, earlier diagnosis, and treatment.
Phase I safety and preliminary efficacy of PM1003, a bispecific antibody targeting PD-L1 and 4-1BB, in patients with advanced solid tumors.
Authors: Xue Junli , Sun Yuping , Li DaPeng , Guo Ye 
Published: June 2023

e14511 Background: PM1003 is a VHH-based anti-PD-L1/4-1BB bispecific antibody. The anti-4-1BB VHH arm binds to a unique epitope at the CRD4 region of 4-1BB, activating 4-1BB signals through cross-linking in the presence of PD-L1 that is often upregulated in the tumor microenvironment, thus avoiding harm to healthy tissues. This is the First In Human study of PM1003. Methods: This study was conducted with a standard 3+3 dose escalation design (Part A: single doses of 0.02, 0.1, 1, 3, 6, and 10 mg/kg for DLT evaluation after 3 weeks followed by Q2W for further administration) and dose expansion (Part B). For Part A, the primary endpoint was safety and tolerability with secondary endpoint of ORR per RECIST 1.1. For Part B, ORR per RECIST 1.1 was the primary endpoint and the secondary endpoints were safety and PK. Results: As of February 9, 2023, a total of 17 subjects have received at least 1 dose of PM1003, including 16 subjects in Part A (3 subjects in each of the 0.02, 0.1, 1, 3 mg/kg dose levels respectively and 4 subjects in 6 mg/kg), and 1 subject in Part B (1 mg/kg Q2W). In Part A, no DLTs were observed up to 6 mg/kg. Of the 17 patients, TRAEs occurred in 15 subjects (88.2%), ≥ Grade 3 TRAEs occurred in 5 subjects (29.4%). No patient discontinued PM1003 administration due to TRAE. The most common TRAEs were anaemia (35.3%), neutrophil count decreased (29.4%), white blood cell count decreased (29.4%), platelet count decreased (29.4%), fatigue (23.5%). 11 subjects completed at least one efficacy evaluation in part A. The median duration of PM1003 exposure was 9.9 weeks (range, 3.1-31.1 weeks). The ORR per RECIST 1.1 was 9.1% with a DCR of 54.5%. Preliminary evidence of antitumor activity has been observed in 1 subject with gastric cancer (1 mg/kg Q2W) who was enrolled after previous surgery, chemotherapy, anti-PD-1 and anti-HER2-ADC treatment, and had a partial response of 87.8% in target lesion reduction during the first efficacy evaluation (7 weeks) after PM1003 treatment. T1/2 of PM1003 of 1 mg/kg and 3 mg/kg dose level is 6.3 and 12.8 days, respectively. Receptor occupancy of PD-L1 in the 1 mg/kg and 3 mg/kg cohorts reached saturation at 336 hours after the first single dose and maintained at an almost stable state. Conclusions: PM1003 was well-tolerated up to 6 mg/kg and has shown preliminary anti-tumor activity in a patient who was previously treated with multiple drug modalities including anti-PD-1. The dose-escalation at 10 mg/kg and dose expansion are ongoing. Clinical trial information: ChiCTR2100052887 .