bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of border zone stereotactic radiosurgery with bevacizumab in patients with recurrent or progressive glioblastoma multiforme.
Authors: Mantica Megan , Drappatz Jan , Lunsford L. Dade , Lieberman Frank S. , Niranjan Ajay 
Published: June 2023

e14020 Background: This phase II trial was performed to assess the efficacy of Border Zone Stereotactic Radiosurgery (BZ-SRS) with bevacizumab by overall survival (OS) in patients with recurrent or progressive glioblastoma (GBM) following conventional upfront management. Methods: Patients with histologically confirmed GBM with recurrent disease, received prior first-line treatment with surgery/biopsy, fractionated radiotherapy and chemotherapy, ≥ 2 months since completion of radiotherapy and eligible for SRS were enrolled. Bevacizumab 10mg/kg was given one day before, day 14 and then every 14 days until disease progression. 1 to 14 days before BZ-SRS procedure, patients underwent standard brain MRI /MRS. MRS with measurement of choline-to-N-acetyl aspartate index (CNI) area ≥ 3 was targeted for SRS using standard MRI targeting. Results: From 2015-2017, sixteen patients were enrolled. The median age was 62 (range, 48-74Y). 3 of 16 (0.188) participants experienced grade 2 unacceptable toxicity. The median OS was 11.73 months. No survival difference is seen compared with the University of Pittsburgh historical controls. PFS-6 and OS-6 were 31.2% (p=0.00294) and 81.2%(p= 0.058), respectively. Of 13 evaluable for best response: 1 complete response (p=0.077), 4 partial responses (p=0.308), 7 stable disease (p=0.538), and 1 progressed disease (p=0.077). 11 of 16 participants had MRS scans with an estimated probability that MRS changes a treatment plan of 0 (0,0.285). Conclusions: BZ-SRS with bevacizumab was feasible and well tolerated. There is no significant survival benefit using BZ-SRS with bevacizumab compared to historical controls. Secondary analysis revealed a trend toward improved PFS-6, but not OS-6. MRS scans did not result in any changes in SRS treatment plans. Clinical trial information: NCT02120287 .
Homologous recombination-related (HRR) gene mutations in patients with glioma and their relevance to genomic characteristics, tumor mutation burden (TMB), and prognosis.
Authors: Zheng Zhiming , Li Mengmeng , Zhang Qin , Luo Ningning , Qi Yingxue , Sun Tingting , Qi Chuang 
Published: June 2023

e14023 Background: Homologous Recombination Repair (HRR) is one of the core repair methods for DNA double strand damage and the mutations of HRR pathway gene may be the main cause of many cancers. However, there is little research on the potential correlation between the molecular characteristics of HRR pathway genes and glioma. Our study explored HRR gene mutations in glioma patients and its relevance to genomic characteristics, tumor mutation burden (TMB) and prognosis. Methods: Samples from 367 glioma patients with a median age of 46 were detected by 551-gene panel or whole-exome sequencing (WES), and the WES data of 894 glioma patients were extracted from TCGA database ( http://cancergenome.nih.gov ). Among 367 glioma patients, 151 patients occurred HRR somatic mutations. Among them, 47.68% (72/151) patients carried HRR related pathogenic mutation (P/LP), and 52.32% (79/151) patients carried HRR benign/likely benign/variant of uncertain significance mutations (B/LB/VUS). The patients were divided into two groups according to whether patients carried HRR related pathogenic mutation, HRR P/LP group (72) and Non-HRR P/LP group (295). The differences of genomic characteristics, TMB and prognosis between HRR P/LP group and Non-HRR P/LP group were analyzed. Results: In 151 glioma patients harboring HRR somatic mutations, PTEN had the highest mutation frequency (49%; 74/151), followed by CHEK2, DNMT3A, BRCA2 and ATM, with mutation frequency of 11% (17/151), 10% (15/151), 9% (14/151）and 9% (14/151). Patients of HRR P/LP group and HRR B/LB/UVS group showed a significant difference at HRR pathway genes, including PTEN, RAD50, MSH6 and RAD21. In addition, differences of non-HRR pathway genes in HRR P/LP group and Non-HRR P/LP group were found. The mutation frequency of these differential genes was generally high in HRR P/LP group. However, compared to Non-HRR P/LP group, the mutation frequency of IDH1 in HRR P/LP group was significantly higher (Non-HRR P/LP 32% VS HRR P/LP 10%; P＜0.0001). The TMB value in Non-HRR P/LP group was significantly higher than that in HRR P/LP group (P＜0.0001), and the same trend of TMB in two groups was discovered in TCGA cohort (P＜0.0001). Importantly, a significant difference of overall survival (OS) in TCGA database was found between HRR P/LP group and Non-HRR P/LP group (P＜0.0001, HR =2.17, 95%CI: 1.54-3.06), and the median OS were 17.6 and 34.9 months, respectively. Conclusions: This study showed HRR pathway genes status was significantly related to the genomic characteristics, TMB and prognosis of glioma patients. Compared to patients in HRR P/LP group, patients in Non-HRR P/LP group had higher mutation frequency of IDH1, lower TMB value and better prognosis. The relationship between HRR pathway genes and glioma needs to be further explored.
Results from the first step of a phase II study of vaccination with autologous dendritic cells loaded with autologous tumour homogenate in glioblastoma.
Authors: Ridolfi Laura , Gurrieri Lorena , Riva Nada , Bulgarelli Jenny , De Rosa Francesco , Guidoboni Massimo , Fausti Valentina , Ranallo Nicoletta , Tazzari Marcella , Petrini Massimiliano , Granato Anna Maria , Pancisi Elena , Foca Flavia , Dall'Agata Monia , Amadori Elena , Cortesi Pietro , Gamboni Alessandro , Pasini Giuseppe , Ibrahim Toni , Tosatto Luigino 
Published: June 2023

e14025 Background: Glioblastoma (GBM) is a poor prognosis malignant grade IV glioma. After surgical resection, standard therapy consists of concomitant radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Multiple phase I/II trials and at least 3 meta-analysis showed improved survival (OS) and progression free survival (PFS) with DC vaccination in High-grade gliomas (HGGs) patients (pts). In pts developing antitumor immunity, DC vaccination increases the amount of intratumoral activated cytotoxic T lymphocytes and decreases the number of FoxP3 positive regulatory T cells. Based on these data we have developed a phase II protocol with DC vaccine concomitant to standard RT-CT in pts who have undergone radical surgery for GBM. Methods: This is a single-arm, monocentric, phase II trial of a DC vaccination integrated to standard therapy in resected GBM pts. All pts receive a dendritic cell vaccine loaded with autologous tumor homogenate for up to one year. The vaccine administration starts at the end of the RT-CT (Induction Phase) and then is alternated to TMZ cycles (Maintenance Phase). Primary end points are PFS and safety, among secondary end points there are the in vitro (Elispot, Plasma Cytokines, Tumor tissue analysis) and in vivo (DTH skin test) Immune response evaluations. A Simon's two-stage design has been used for the sample size calculation. In the first stage, 9 patients have been accrued and a total of 28 patients will be enrolled at the end of the second step. Results: From July 2021, the 9 pts of the first step has been enrolled, 4 females and 5 males with median age of 58 years. Five pts had no MGMT mutation. All 9 pts concluded the induction phase. To November 2022 four pts have progressed with a median PFS, from the date of leukapheresis, of 6.5 months (3.2-NE). DTH test became positive in 5 out of 9 evaluable pts. Median OS from the date of surgery was 11 months. No gr 3-4 vaccine related toxicities have been observed and gr 1-2 toxicities were mostly due to local skin reactions. Conclusions: On the basis of the results described above and the vaccine favorable toxicity profile the Study Team decided to proceed with the second step. Clinical trial information: EUCTR220-003755-15 . [Table: see text]
The activity and safety of anlotinib for patients with recurrent malignant glioma: A single-center, retrospective study.
Authors: Sun Xudong , Li Min-Jie , Zhang Xue-ying , Shen Yue-feng 
Published: June 2023

e14032 Background: Anlotinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) 1/2/3, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR) 1/2/3/4, c-Kit, and Ret. We report results from this retrospective study to determine the efficacy and tolerability of Anlotinib as a treatment for recurrent malignant glioma (rMG). Methods: A total of 26 eligible patients who relapsed from the standard chemoradiotherapy regimen (TMZ and radiotherapy) after surgery because of tumor located in the eloquent brain areas were enrolled in this study between May 2020 and August 2022. Patients were subjected to a concurrent treatment of Anlotinib (12mg qd) until disease progression or intolerable toxicity. Efficacy was evaluated using Response Assessment in Neuro-Oncology criteria for high-grade glioma. Safety was assessed using NCI-CTCAE 5.0. Survival was estimated with the Kaplan-Meier curve and log-rank test. Results: In total, 26 (11 male, 15 female) patients with recurrent malignant glioma were enrolled. The disease control rate was 84.6% (95%CI 36.9%-76.7%) and the objective response rate was 57.7%(95%CI 65.1%-95.6%). The median progress-free survival (PFS) for all patients was 9.0 months (95%CI 2.88-15.19). The most common treatment-related adverse events were hand-foot syndrome (38.5%), Weakness (38.5%), hypertension 30.8%) and there were no Grade ≥3 toxicities. Conclusions: The present study showed that anlotinib had a promising efficacy and favorable tolerability in treat rMG. Further randomized controlled clinical studies are needed to confirm the efficacy of Anlotinib for the treatment of rMG.
Genomic landscape of CDK6 amplification and its potential prognostic value in adult-type diffuse gliomas.
Authors: Yuan Xi , Que Tianshi , Yi Guozhong , Li Zhiyong , Zheng Haojie , Liu Yawei , Wang Xiaoxuan , Zhang Xing , Huang Guanglong 
Published: June 2023

e14038 Background: Glioma is commonly described as a disease of neuroglial cell proliferation. And the gene related to cell cycle pathway alter frequently in glioma including CDKN2A/B, CDK4 and CDK6. CDKN2A/B homozygous deletion is proved to be associated with worse survival in IDH-mut gliomas and meningiomas. However, the correlation between CDK4/6 amplification and the prognosis of glioma remains unclear. Herein, we explored the distribution of CDK4/6 alterations and whether they are the prognostic biomarker of glioma. Methods: A total of 90 patients with adult-type diffuse glioma were enrolled to this retrospective study from our center. Whole genome sequencing (WES) was performed to identify the mutations of the cohort. Results: CDK4 and CDK6 amplified in 17 (18.9%) and 12 (13.3%) patients, respectively. Four patients harbored both CDK4 and CDK6 amplification. The Cox multivariate regression revealed only CDK6 amplification was the independent factor (HR 4.0, 95% CI 1.1-15.2, p=0.041) of overall survival (OS). Interestingly, CDK6 amplification occurred easier in female and trended to be co-mutant with CDKN2A/B homozygous deletion. CDK6 amplification was found to be significantly associated with shorter OS ( p<0.05) of glioblastoma (GBM). Although TERTp was not related to the OS of GBM according to TCGA, patients harboring both TERTp and CDK6 amplification had the significant worst OS ( p<0.001). Conclusions: Our study compared the mutational characteristics of gliomas with CDK4/6 alterations and demonstrated the potential prognostic value of CDK6 amplification, and provide the new basis of precise diagnosis and treatment in gliomas.
Anlotinib for patients with newly diagnosed glioblastoma with unmethylated MGMT promoter: An open-label, single-center, phase 2 clinical trial.
Authors: Yang Kunyu , Wu Bian , Zhang Zhanjie , Peng Gang , Huang Jing , Hong Xiaohua , Ding Qian , Shi Liangliang , Wang Xuan , Zhao Hongyang , Jiang Xiaobing 
Published: June 2023

e14039 Background: Glioblastoma (GBM) is the most common primary malignant brain tumor and one of the most deadly forms of cancer in humans. Given the temozolomide’s minimal benefit in O6-methylguanine-DNA Methyltransferase (MGMT) unmethylated GBM, new and effective therapies are urgently needed. In this study, we aimed to assess the safety and efficacy of anlotinib, a novel multitarget tyrosine kinase inhibitor for VEGFR, PDGFR, and c-Kit, in patients with MGMT unmethylated GBM. Methods: This was an open-label, single -center, single-arm, phase 2 trial. Eligible patients included those aged 18 to 70 years who had newly diagnosed histologically confirmed GBM with unmethylated MGMT promoter region. The cutoff value ≥ 10% was used to classify MGMT methylated vs. unmethylated cases. After initial surgical resection, patients with GBM received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and anlotinib (beginning on day 43 after surgery, at a dose of 12 mg orally once daily on days 1-14 of a 21-day cycle), followed by 6 cycles of maintenance therapy with anlotinib (at a dose of 12 mg orally once daily on days 1-14 of a 21-day cycle). Patients were re-evaluated every six weeks. The primary endpoint was progression-free survival (PFS), which is defined as the interval from the initiation of anlotinib treatment until the date of disease progression or death. The secondary endpoints were overall survival (OS) and safety. Standard Response Assessment in Neuro-Oncology (RANO) criteria were used to determine tumor response and progression. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. This trial was registered with chictr.org.cn, ChiCTR2000040116. Results: A total of 32 participants were enrolled from September 2020 to June 2022. All patients were with IDH wild-type and MGMT unmethylated status. The median age was 50 years (range, 27-65), and 19 (59.4%) were male. The median follow-up duration was 14.8 months (range, 5.5-23.7). The median PFS was 10.5 months (95%CI: 8.5-12.5), and the median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 13 (40.6%) patients of patients and grade 3 adverse events were observed in 4 (12.5%) patients. The most common toxicities were hypertension (13 [41%]), hand-foot syndrome (12 [38%]), hematuresis (9 [28%]) and liver dysfunction (5 [16%]). Grade 3 therapy-related adverse events included liver dysfunction (2 [6.3%]), hypertension (1 [3.1%]), hand-foot syndrome (1 [3.1%]). No grade 4-5 or unexpected adverse events were observed. Conclusions: This preliminary analysis suggested that anlotinib had promising efficacy and favorable tolerance as treatment of newly diagnosed GBM with unmethylated MGMT promoter. Clinical trial information: ChiCTR2000040116 .
Mutation profiling of gliomas based on sex, age, and family history.
Authors: Fan Xue , Yang Ming , Zhang Xiaoni , Li Hui , Wan Xuebin , Liu Yuanyuan , Zhou Shuxiong 
Published: June 2023

e14041 Background: The gender, age and family history of patients are important factors leading to the mutation of tumor-related genes. Currently, the relationship between these factors and tumor gene mutations in glioma is unclear. Therefore, we identified the effect of gender, age, and family history on cancer-susceptibility gene mutations in patients with glioma through retrospective analysis. Methods: A total of 735 FFPE tissue samples were collected from 2019 to 2022 in glioma patients, and sequenced by HapOnco StarPanel NGS Assay (covering 1326 genes + 3 viral sequences). Results: (1) These mutations were categorized into four subgroups according to the age of the patients. In the 0-20 years group, the main mutated genes were TP53 (63.64%), BRAF (36.36%), and H3F3A (22.73%) in females (n = 22) and TP53 (26.92%), BRAF (46.15%) and H3F3A (19.23%) in males (n = 26), respectively. In the 21-40 age group, the gene mutation rates of TP53, IDH1, and TERT were 71.43%, 58.57%, and 21.43% in female (n = 70), whereas these genes ( TP53, 72.90%; IDH1, 63.55%; TERT, 35.51%) displayed higher mutation frequency in males (n = 107). In the 41-60 age group, TERT (61.70%), TP53 (43.97%), and IDH1 (36.88%) in females (n = 141) showed obvious difference compared with that ( TERT, 54.33%; TP53, 47.12%; IDH1, 42.31%) in male (n = 208). Aged patients, especially those over 61 years, the most mutated genes were TERT (63.08%), EGFR (60.00%), and TP53 (49.23%) in female (n = 65), respectively. However, the most commonly mutated genes in male presented apparently different than the genes in female such as LRP1B, CSMD3, SYNE1, NF1, ATM, PTEN, RB1, TERT, MET, and TP53. (2) Generally, the peak incidence of patients with glioma is between 41-60 years old. We found the percentage of the total incidence of glioma patients was associated with the family history (positive, 56.25%; negative, 47.68%). Conclusions: The gene mutated rates were depending on the age, sex, and family history in glioma, which might reveal potential effect for biomarker detection in combination with these categories in clinical.
Concurrent chemoradiation and adjuvant chemotherapy in newly diagnosed glioblastoma multiforme: A retrospective analysis of single center.
Authors: Iruarrizaga Eluska , Iza Estibaliz , Mañe Joan Manel , Rubio Itziar , Novo Eneko , Lombardero Lara , De Miguel María José , Muñoz Alberto 
Published: June 2023

e14053 Background: The standard of care of glioblastoma multiforme (GBM) first line therapy is maximum safe debulking and posterior treatment based in concurrent chemo-radiation (Qt-Rt) followed by temozolomide-based chemotherapy. Despite a complete resection and adjuvant treatment, overall survival (OS) in patients (pts) with GBM is poor and it depends on tumor biology and patient characteristics. We analyzed retrospectively clinical and tumor biology characteristics of pts with GBM treated in our center with Qt-Rt +/- adjuvant Qt and their impact in OS. Methods: From November-2016 to October-2022, we collected data for 82 pts (median age: 60 years) who underwent Qt-Rt exclusively (25 patients) or Qt-Rt and adjuvant temozolomide (57 patients). Pts characteristics are detailed. Results: In multivariate analysis, significant difference of OS were observed in function of type of surgery (better OS in R0; p=0.015), performance status (better OS in PS 0-1; P=0.006), MGMT methylation (better OS in methylated; p=0.037), ATRX status (better OS in negative; p=0.05). No differences were founded in function of TERT (p=0.47) or p53 status (p=0.57). OS was significantly increased in pts treated with Qt-Rt and adjuvant Qt (17.7 +/- 1.7 months) vs Qt-Rt exclusively (11.35 +/-1.62 months) (p=0.013). After Qt-Rt treatment, radiological response was (%): no evidence of disease 13.4/partial response 6.1/stable disease 58.5/progressive disease 18.3/not evaluated 2.4. Most relevant adverse event G3/4 during Qt-Rt (%): thrombocytopenia 7.31, neutropenia 8, leukopenia 3.65, anemia 2.4, thrombosis 2.4. There were 2 toxic death (infection grade 5). After Qt-Rt, 57 pts received adjuvant treatment (median number of cycles: 5; range 1-15). Most relevant toxicity G3/4 during this therapy was (%): asthenia 3.05, anorexia 1.75, thrombocytopenia 5.26, neutropenia 3.05, leukopenia 1.75. There was 1 toxic death (infection G5). Pts that received 4 or more cycles of adjuvant temozolomide had a significant impact on OS versus those that completed 3 or less cycles (19.28 +/- 2 months vs. 12.05 +/- 1.5 months; p=0.022). Conclusions: Temozolomide-based chemotherapy in GBM is an effective and safe therapy and the premature interruption of this treatment may impact on OS. It is essential to know patient characteristics and tumor biology in order to identify patients that will beneficiate from this treatment.[Table: see text]
Pre-clinical efficacy of the first glyco-humanized oncolytic polyclonal antibody (XON7) in onco-hematology.
Authors: Ciron Carine , Shneiker Françoise , Duvaux Odile 
Published: June 2023

e14519 Background: Polyclonal antibodies pAb were shown to possess oncolytic properties a century ago with reported clinical responses. More recent pre-clinical models confirmed pAb efficacy though their ability to tackle complex target antigens. The emergence of escape variants could be minimized by multi-targeting of tumor cells with pAb, which would be more efficient than mAb at mediating effector functions for target destruction. However, the use of heterologous pAb is limited by their immunogenicity. Glyco-humanization (GH) solves this issue and allows to reconsider the potential of pAb in oncology. 3 GH-pAb have already been introduced in clinic in non-oncology settings, with a good safety profile. XON7 is a new GH-pAb targeting cancer cells. Methods: Complement dependent cytotoxicity (CDC) and apoptosis against various tumor cell lines and PBMC from healthy donors were tested with XON7 at increasing concentrations (6,25 µg/mL to 400 µg/mL) Specific binding to human tumors was assessed by immunochemistry on tissue micro-array (13 sections of original tumor, 13 healthy tissues). Cross-cancer activity was evaluated on biopsies from patients with solid tumor or blood cancer: CRC (n=63), NSCLC (n=30), Osteosarcoma (n=4), pancreatic (n= 48), GIST (n=2), AML (n=10), DLBCL (n=7). Xenograft mice model: XON7 efficacy was tested in several sub cutaneous xenograft models in NMRI nude mice (n=10 per group) using A549: non-small-cell lung cancer, HCT-116: colon cancer, LnPac: prostate cancer, KMS-12-BM: myeloma, T1301: T cell lymphoma. Treatments (35mg/kg, twice a week) were given for 4 weeks once the tumor reached 50 mm3. Results: XON7 induced specific human tumor cell lines CDC (IC50=50ug/mL) and apoptosis (IC50= 100ug/mL) up to 100% of the cells, without cross-reactivity with healthy human cells. XON7 targets several patients’ tumoral tissues. In vivo, XON7 induces a significant reduction of tumor growth ranging from 40 to 90% across all tested tumors. Conclusions: Immunotherapy with XON7 could be a novel therapeutic approach to fight solid tumors and hematological malignancies. [Table: see text]