bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and characteristics analysis of CDKN2A/B deletion in glioma.
Authors: Zhuang Dongxiao , Han Tiantian , Guo Didi , Kong Rongrong , Chen Siqi , Dong Yuwei , Wang Mengjuan , Ding Ran , Deng Wanglong , Bu Fanfeng 
Published: June 2023

e14026 Background: Glioma is the most common type of brain malignancy in adults. The 5th edition of the World Health Organization (WHO) highlighted the homozygous deletion of the CDKN2A/2B as a clinically important molecular alteration in IDH-mutant glioma. In the study, we reported the prevalence and characteristics analysis of CDKN2A/B deletion in glioma. Methods: This study retrospectively analyzed the genomic alteration of 2390 Chinese glioma patients during 2019-2022. Next-generation sequencing (NGS) of 131-gene profiling was performed to detect gene mutations in tumors of the patients. Patients were divided into two groups for copy number (CN) variation set, as heterozygous deletion (CN> 0.5, HET-del) or homozygous deletion (CN≤ 0.5, HOM-del) group. Results: A total of 743 (31%) cases were detected with CDKN2A/B deletion, 21 cases were children (< 18 years old), and 722 cases were adults, with a mean age of 53 years (0-85 years). CDKN2A/B deletion showed a higher frequency in the subgroup of IDH-wildtype glioma compared with IDH-mutant glioma in adults (39% vs. 15%, p<0.005). The age showed no significant difference between CDKN2A/B HET-del (n=420) and HOM-del (n=323) patients (average age: 53, p = 0.74). In both of the two groups, the most frequently somatic mutated genes were TERT, EGFR, PTEN. However, NF1 mutations were significantly enriched in the HET-del group (21% vs. 12%，p<0.005). Conclusions: Taken together, CDKN2A/B deletion were found in 31% glioma patients and showed higher frequency in IDH-wildtype glioma. NF1 mutations were significantly enriched in the HET-del group, which may reveal distinct prognosis and pathogenic mechanisms in glioma.
The efficacy and safety of anlotinib combined with bevacizumab in treatment of recurrent isocitrate dehydrogenase wildtype glioblastoma: A retrospective analysis.
Authors: Li Shuo , Lai Long , Hou Zhiwei , Tao Rongjie , Qu Bing , Zhang Hui , Yu Jinming 
Published: June 2023

e14028 Background: Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor with a 5-year survival rate of 5%. There is no standard and effective treatment for recurrent GBM. Angiogenesis is recognized as a key event in the progression of GBM. Bevacizumab as an anti-angiogenic monoclonal antibody has been recommended by NCCN guidelines for recurrent GBM. Anlotinib is a small-molecule multi-target tyrosine kinase inhibitor (TKI) which has different function mechanisms and targets with bevacizumab. Therefore, we investigated the clinical efficacy and safety of anlotinib combined with bevacizumab in patients with recurrent IDH-wide type (wt) GBM on the basis of TMZ treatment. Methods: We retrospectively analyzed the clinical data of 18 patients with IDH-wt GBM in Shandong Cancer Hospital and Institute from 2019 to 2022. The primary endpoint was progression-free survival (PFS) and overall survival (OS) for combination treatment. The secondary endpoint was 6-months PFS rate, 1-year OS rate, objective response rate (ORR), disease control rate (DCR), OS and safety and toxicity profile. Results: All patients were diagnosed as WHO grade IV IDH-wt GBM and the median age of all patients was 55 years (range 39-76). Patients with recurrent GBM were first treated with anlotinib, followed by bevacizumab when patients developed progression or cerebral edema. In the overall population, the median OS for overall patients is 27 months, and the median survival time after first recurrence is 13.3 months. The median survival time of anlotinib treatment and combination treatment is 15.6 months and 12 months, respectively and the median PFS is 14.3 months and 9.1 months, respectively. The ORR for combination treatment was 27.8%, and 6-months DCR was 77.8%. The last follow-up date was October 15, 2022. By the last follow-up date, 3 patients were continuing anlotinib combined with bevacizumab treatment with no disease progression. The 6-months PFS rate was 78.9%, and the 1-year OS rate was 44.4%. The treatment-related adverse events (AEs) were shown in Table 3. The main AEs was bone marrow suppression (83.3%, 15/18), most of which were grade I and II (50%, 9). The AEs were relieved by adjusting the drug dose and symptomatic treatment. There were no treatment related deaths. Conclusions: Our study reported the clinical effect of anlotinib combined with bevacizumab treatment in recurrent GBM patients on the basis of TMZ treatment in a real-world setting. This is the first attempt to conduct dual antiangiogenic treatment in GBM patients. We demonstrate a promising result and suggest that this combination treatment may be a novel and safety treatment option for recurrent IDH-wt GBM patients.
Tumor treating fields (TTFields) therapy skin safety and prevention strategy using a fractionated schema protocol (3-days on/1-day off), effect on skin adverse events.
Authors: Gatson Na Tosha N. , Ornelas Sara , Manikowski Jesse , Toms Steven A , Leese Erika 
Published: June 2023

e14030 Background: Tumor Treating Fields (TTFields) therapy is a locoregional, noninvasive modality currently approved for newly diagnosed (nd) and recurrent (r) CNS WHO grade 4 astrocytomas and glioblastoma (GBM), as well as pleural mesothelioma. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, and are generated by a portable device, delivered by skin-placed arrays. TTFields therapy is not associated with systemic toxicities, nor significant toxicities to healthy tissues or organs within the body; the most commonly associated adverse event (AE) is mild-to-moderate skin irritation beneath arrays, which can typically be managed with appropriate prophylaxis and timely intervention strategies (Lacouture et al 2014 and 2020). Here we report safety outcomes with a novel 3-day on/1-day off protocol strategy that aims to prevent and minimize skin irritation and limit treatment interruptions. Methods: In this dual center, retrospective analysis, adult patients with grade 4 ndGBM or rGBM followed a 3 days-on (72-80 h) and 1 day-off (16–24 h) TTFields therapy use schedule, with skin specific wound prevention guidance (barrier forming moisturizing topical creams and selenium-based shampoos) during the ‘off day’. Information on the presence and severity of skin AEs was collected from patient charts. Results: Adult patients (N = 76) received TTFields therapy with the 3-on/1-off protocol between 2015 and 2021 at 2 healthcare centers in the United States. Median age was 57 years (range 25–81 years) and mean time on TTFields therapy was 73 weeks. Skin AEs occurred in 5% of patients on the 3-day on/1-day off protocol, as compared to 16% and 52% reported in the randomized, phase 3 EF-11 (NCT00379470) and EF-14 (NCT00916409) studies in patients with rGBM and ndGBM, respectively. As in the clinical studies, most AEs were mild in nature. All patients who had a skin AE, prior to starting the 3-days on/1-day off protocol, received treatment to resolve the AE. In addition, no patients had to discontinue TTFields therapy or modify array placement due to skin AEs while on the 3-on/1-off protocol. Conclusions: These real-world clinical practice data confirm the positive known safety profile of TTFields therapy and are consistent with findings from clinical studies. Mild-to-moderate skin irritation is the AE most commonly associated with TTFields therapy, which is mostly manageable and resoluble. These data suggest that skin irritation could be further reduced with active preventative approaches, as described in the fractionated schema (3-days on/1-day off) protocol.
Evolution of genomic profiles in primary and recurrent brain gliomas.
Authors: Lizcova Libuse , Vidlakova Denisa , Lhotska Halka , Svobodova Karla , Hodanova Lucie , Cechova Hana , Aghova Tatiana , Ransdorfova Sarka , Pavlistova Lenka , Netuka David , Hrabal Petr , Kramar Filip , Zemanova Zuzana 
Published: June 2023

e14042 Background: Diffuse gliomas are highly heterogenous tumors with variable biological behaviors, including high intratumor and extratumor heterogeneity, and with occurrence of recurrent lesions in majority of patients. During disease progression, gliomas undergo cellular and genomic evolution with newly acquired genetic properties. However, the mechanism of this complicated process associated with treatment failure is poorly understood. In this retrospective study, we performed cytogenomic analyses of primary and recurrent tumors in five patients with diffuse glioma who underwent surgical resections or biopsies of multiple recurrences. Methods: One primary and at least two recurrent freshly resected tumor tissues from each patient were analyzed using combination of cytogenomic methods. To assess specific and random copy number alterations (CNAs), I-FISH (Abbott Molecular, MetaSystems), array CGH/SNP (Agilent) and MLPA (MRC Holland) were performed. Methylation of MGMT promoter was investigated by methylation-specific MLPA (MRC Holland) and mutations of 67 genes associated with solid tumors were assessed by target NGS (Archer VariantPlex Solid Tumor, Invitae). Results: All five patients (three men and two women) experienced recurrence with newly acquired genetic or epigenetic changes. We observed a higher frequency of CNAs in recurrent gliomas than in primary tumors. Moreover, several aberrations were not detected in recurrence despite being found in earlier samples. As a primary event we proved mutation R132H of IDH1 gene. In addition, we detected methylation of the MGMT promoter, CDKN2A/B homozygous deletion, and RB1 deletion as later events that were probably associated with higher tumor grades. Besides the typical genomic changes, we detected many aberrations with unknown or unclear prognostic relevance (e.g. inframe deletion in TP53, p.Met243_Asn247del, etc.). The progression to a higher grade of glioma occurred in four patients. Conclusions: The evolutional patterns in glioma depend on clonal selection caused by CNAs, mutations, genetic drift, intratumor heterogeneity and/or the patient’s treatment. Recurrence may arise from one major tumor clone or from one or more subclones within the primary tumor through. Integrated cytogenomic analyses of genetic/epigenetic profiles of primary and all recurrent tissues can contribute to a better understanding of mechanisms responsible for these processes and to identification of new alterations related to gliomas progression and/or resistance to treatment. These biomarkers could subsequently serve as new therapeutic targets for personalized treatment.
Overcoming temozolomide resistance in glioblastoma through selective inhibition of phosphoinositide 3-kinase catalytic subunit.
Authors: Hutchings Kasen Reed , Beck Patrick , Pridham Kevin J , Liu Min , Owens Joseph , Tegge Allison , Kelly Deborah F , Sheng Zhi 
Published: June 2023

e14045 Background: Glioblastoma is one of medicine's most difficult-to-treat cancers due to its inevitable resistance to chemotherapies, such as temozolomide (TMZ). Tumor resistance to TMZ often comes from overactivation of phosphoinositide 3-kinase (PI3K), making this enzyme an ideal anti-cancer drug target; however, in practice, non-selective targeting of PI3K has resulted in undesirable clinical outcomes. Therefore, it is necessary to explore each subunit of PI3K to determine their effect on chemoresistance in order to develop therapeutics to overcome said resistance. PI3K has four homologous yet functionally distinct catalytic subunits: p110α, p110β, p110δ, and p110γ. Preliminary in silico analysis of each subunit has demonstrated that p110β is more highly expressed in glioblastoma than the other subunits. Here we report that TMZ resistance in glioblastoma is driven primarily by activation of p110β. Methods: Glioblastoma cell lines with high p110β levels (SF295 and U87MG) and low p110β levels (A172 and LN229) were cultured. CRISPR-Cas9 was used to knockout p110α, p110β, or p110δ in cultured cell lines. The viability of cultured cells was measured using an MTS viability assay. Newly cultured wild-type cells were treated with IC50 doses of selective p110β inhibitor TGX-221 and TMZ. Mice bearing SF295 xenograft tumors were treated with DMSO, TGX-221, and/or TMZ. A Bliss model of independence was used to assess the association between TGX-221 and TMZ with synergistic and antagonistic patterns measured using excess over Bliss (EOB) scores. Results: There was a significant reduction in viability among SF295 p110β-knockout cells (p < 0.001) and an additive cytotoxic effect following treatment with TMZ. The LN229 p110β-knockout cells treated with TMZ did not reduce cell viability. Similarly, no substantial declines in viability were observed in the p110α- or p110δ-knockout cells before or after TMZ treatment in either cell line. In newly cultured wild-type p110β-high and p110β-low glioblastoma cell lines, TGX-221 or TMZ alone were insufficient to inhibit cell viability; however, when combined, TGX-221 and TMZ synergistically decreased cell survival with an EOB of 45.5% in U87MG cells and 26.3% in SF295 cells. No additive effects were detected in the p110β-low cell lines following TGX-221 and TMZ treatment. Additionally, TGX-221 combined with TMZ resulted in a drastic reduction in xenograft tumor growth, which was significantly greater than TGX-221 (p < 0.02) or TMZ (p < 0.003) treatment alone. Conclusions: Inhibition of p110β via CRISPR-Cas9 knockout or pharmaceutical blockade restores TMZ sensitivity in p110β-high glioblastoma cells and xenograft glioblastoma tumors. These results demonstrate the varying importance of PI3K catalytic subunits and necessitate further exploration into p110β as a potential drug target to overcome chemoresistance in glioblastoma.
A multicenter retrospective study of the duration of adjuvant temozolomide in IDH-mutant gliomas.
Authors: Densmore Isabella , Lanman Tyler Ashford , McGranahan Tresa 
Published: June 2023

e14048 Background: Gliomas with isocitrate dehydrogenase (IDH) mutations have improved prognosis and are more treatment responsive compared to IDH wild-type gliomas. For glioblastoma (IDH wild-type glioma), Stupp protocol has demonstrated superiority with 6 cycles of adjuvant temozolomide (TMZ). However, recommended duration of TMZ for IDH mutant gliomas is not well-defined, with studies such as RTOG 0424, CATNON, and CODEL extending treatment up to 12 cycles. Prolonged TMZ duration following radiation therapy (RT) is associated with increased toxicity including both financial (cost of drug, lab work, and visits) and drug side effects including cytopenias. We aimed to evaluate for any differences in survival between patients treated with more than 6 cycles of TMZ and those treated with 6 or fewer. Methods: We conducted a multicenter retrospective study of patients treated at the University of Washington and Stanford Medical Center for oligodendrogliomas (oligo) and IDH mutated astrocytomas (astro) using World Health Organization 2016 molecular diagnostic criteria including IDH mutation. Other inclusion criteria were grades 2 and 3, as well as treatment with RT (with or without concurrent TMZ) followed by adjuvant TMZ monotherapy with number of cycles documented. Survival probability, mean overall survival (mOS) and mean progression-free survival (mPFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in Prism GraphPad comparing >6 cycles of adjuvant TMZ and ≤6 cycles. Results: Of 153 patients treated with both XRT and adjuvant TMZ, 88 were treated with between 1 and 6 cycles of adjuvant TMZ, while 91 were treated with >6 cycles Treatment duration ranged from 1-12 cycles for oligos, 4-12 cycles for grade 2 astros, and 1-14 cycles for grade 3 astros. mOS of oligos was undefined for those treated with 1-6 cycles and 84 months (m) for those treated with >6 cycles (p=0.1448). mOS of grade 2 astros was 154m for those treated with 1-6 cycles and 162.9m for those treated with >6 cycles (p=0.8864). mOS of grade 3 astros was undefined for those treated with 1-6 cycles and 117m for those treated with >6 cycles (p=0.8003). mPFS of oligos was 93m for those treated with 1-6 cycles and undefined for those treated with >6 cycles (p=0.584). mPFS of grade 2 astros was 79.6m for those treated with 1-6 cycles and 144.56m for those treated with >6 cycles (p=0.610). mPFS of grade 3 astros was 72m for those treated with 1-6 cycles and 79.4m for those treated with >6 cycles (p=0.9596). Conclusions: While this study is limited by power, there was no difference in mOS or mPFS with greater than 6 cycles of TMZ among patients with oligodendrogliomas and IDH mutant astrocytomas. More data is needed to evaluate the optimal treatment duration to maximize survival without over-exposing these patients to toxicities.[Table: see text]
Engineering of mesenchymal stem cells to express cytosine deaminase gene with a selecable marker gene.
Authors: Suh-Kim Haeyoung , Kim Min-Gyeong , Lee Young-jun , Bashyal Narayan , Kim Sung-Soo , Chang Da-Young 
Published: June 2023

e14050 Background: Suicide genes induce apoptosis not only in the cell itself but also in surrounding cells. The former is called the suicide effect and the latter is called the bystander effect. Two major suicide gene strategies currently pursued, cytosine deaminase (CD)/5-fluorocytosine (5-FC) and the herpes simplex virus-thymidine kinase/ganciclovir. Both genes have similar potential to induce suicide effects, but bystander effect is higher in CD/5-FC. Here we show that the level of CD expression/activity influence the anti-cancer activity of CD-expressing cells and further demonstrate the need to use selectable markers during manufacturing of CD-expressing cells. Finally we test whether live microbes harboring the shed selectable marker genes are controllable by commonly used antibiotics. Methods: We introduced a microbial CD gene and puromycin-N-acetyltransferase ( pac) gene to bone-marrow derived mesenchymal stem cells MSCs) using a retroviral vector and selected the transduced cells with 4 ug/mL puromycin for one week. To determine the effect of purity, we varied the ratio of CD-expressing MSCs with naïve MSCs and 5-FC concentration in the culture and on co-cultured glioma cells. To mimic the situation in which the shed pac gene is transmitted to live microbes in vivo, we introduced the pac gene to E. coli and tested the growth of the pac-expressing E. coli using VITEK following the standard protocol M100-S32 in the presence of diverse antibiotics. Results: We found that selection of CD-expressing cells with puromycin during manufacturing process enhanced the bystander (anti-cancer effect). Lowering the purity of CD-expressing MSCs required more 5-FC with higher IC50. Growth of pac-expressing E. coli was completely inhibited by commonly used antibiotics in the hospital. Conclusions: We proved that antibiotic selection is necessary during manufacturing process. We also showed that the risk of transmission of shed pac gene can be manageable with commonly used antibiotics. We propose that using pac selectable marker gene can be beneficial to maintain the purity of engineered cells.
Xenonucleic acid technology in high-sensitivity IDH1/2 mutation detection for glioma molecular profiling.
Authors: Yang Hongjun , Wang Herui , Sang Xueyu , Zhuang Zhengping , Fu Andrew Y. , Sha Michael 
Published: June 2023

e14052 Background: Glioma is a life-threatening primary brain tumor that poses significant challenges for diagnosis and treatment. Certain genetic features, such as the IDH1/2 mutation status (codon 132 of IDH1 and codon 172 of IDH2), can help distinguish between different types of gliomas. IDH1/2 wild-type and mutant gliomas have different prognoses and treatment options, with patients with IDH1/2 mutations typically having a better prognosis and a better response to chemotherapy. However, current available molecular tests for IDH1/2 mutation detection have limited sensitivity, and their application to circulating cell-free DNA has not been well established. Methods: To address these challenges, we have developed a new technology that uses xenonucleic acids (XNA) to achieve high sensitivity and specificity for detecting IDH1/2 mutations. We designed and synthesized a specific XNA probe to block PCR amplification from the IDH1 wild-type allele so that the IDH1 mutant allele can be enriched by Taqman real-time PCR. Results: Our tests showed that the XNA-mediated Taqman Real-time PCR system could efficiently detect IDH1-R132H mutations at a frequency as low as 0.1% (e.g., 7 IDH1-R132H copies out of 7,425 IDH1 copies) in both synthetic DNA fragments and genomic DNA from glioma stem cell lines. Clinical verification and validation studies are ongoing using tissue biopsies and paired plasma circulating cell-free DNA (cfDNA). The results of these studies will further demonstrate the reliability and accuracy of our XNA-based detection technology and its potential impact on patient outcomes. Conclusions: Our innovative technology holds the potential to significantly enhance the diagnosis of gliomas and other cancers. It offers a cost-effective, readily available, and precise diagnostic solution that can be performed by standard pathology personnel using equipment already available in hospital pathology laboratories. We will showcase the innovative capabilities of our XNA-based detection technology and its potential to improve the diagnosis and management of gliomas.
Glioblastoma in elderly patients: A retrospective analysis of survival and response based on molecular and clinical characteristics—Experience in our centre.
Authors: Iza Estibaliz , Mañe Joan Manel , Iruarrizaga Eluska , Rubio Itziar , Fernandez Ricardo , Jiménez Pablo , Mohamed Lamin Failah , Toquero Mikel , Muñoz Alberto 
Published: June 2023

e14054 Background: Glioblastoma (GBM) is the most lethal and the most common malignant central nervous system tumor in adults. The standard treatment includes surgery, radiotherapy (Rt) and temozolomide based chemotherapy (Qt). However, compared with younger population, overall survival (OS) is worse in elderly patients and, additionally, this group is not usually included in clinical trials. Retrospective studies have shown, among other factors, tumor biology and performance status with poorer survival in older population, but it is necessary further research in order to discover prognostic factors and optimize management in this group. Methods: In this retrospective study we analyzed clinical and tumor biology characteristics in older population (≥ 70 years) and we also compared these results with younger population (< 70 years) for the purpose of enhance clinical outcomes. From November-2016 to October-2022, we analyzed 111 patients in our hospital: group A (< 70 years): 80 patients, group B (≥ 70 years): 31 patients. The tumor biology and patient characteristics are described in the table. Results: OS was statistically better in group A (A 13.93 +/- 1.28 months versus B 9.39 +/- 1.45 months; p=0.035). In contrast of A, in B no differences in OS were observed related with type of surgery (p=0.78), MGMT status (p=0.4) or p53 status (p=0.75). However, significant differences in OS were observed in B in multivariate analysis according to modality of adjuvant treatment (greater OS in Qt-Rt+ Qt > Qt-Rt > Rt exclusively > no treatment; p<0.001) and performance status (greater OS in PS 0 > PS 1 > PS 2 > PS 3; p=0.001). There was no differences of OS between A and B if the adjuvant treatment was concomitant Qt-Rt +/- Qt (p=0.81), but with this therapy there was a toxic death (infection Grade 5) in B group. Other relevant toxicities Grade 3/4 in this group with Qt-Rt +/-Qt were: infection 3.2%, thrombocytopenia 12.9%, neutropenia 12.9%, leukopenia 6.45%, anemia 3.2%, thrombosis 3.2% Conclusions: Temozolomide based therapy is an effective and safe option for the treatment of patients ≥ 70 years with GBM. We need to perform prospective trials in this population in order to recognize prognostic and predictive factors to allow better treatment selection.[Table: see text]