bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Difference in presentation of pediatric and adult ependymoma: An NCDB analysis.
Authors: Tuman Jaylin , Anderson Quinton , Hsia Beau , Wu Xinxin , Silberstein Peter T.
Published: June 2023

e14055

Background: Ependymomas originate from ependymal cells and account for 6.2% of primary brain tumors in the pediatric population. Adult and pediatric ependymomas are identical in histology, but present in different sites, with intracranial ependymomas seen in children and spinal ependymomas more frequent in adults. The unique presentation of ependymoma in children warrants exploration separate from adults; however, there is currently limited data providing a baseline understanding of pediatric ependymoma and those that it impacts. The National Cancer Database (NCDB) was analyzed to identify common presentations and demographic characteristics of ependymoma in children. Methods: Patients aged 18 and younger with a diagnosis of Ependymoma (ICD 9391-9394) were identified utilizing the National Cancer Database (NCDB) from 2004 – 2020 for a retrospective cohort analysis (N = 2,098). Demographic factors such as age, sex, race, ethnicity, primary site, insurance status, and surgical procedure were analyzed by descriptive statistics. Additionally, identical NCDB data was identified for patients over 18 years old for use as a comparison factor (N = 8,227). Results: A total of 2,098 pediatric patients were identified with an average age of diagnosis of 7.0 years (SD = 5.609, range = ( < 1) - 18 years) with a higher percentage being male (55.9%) than female (44.1%). The vast majority of cases of pediatric ependymoma originate in the brain (91.2%), followed by occurrences on the spinal cord and cranial nerves (8.8%). This differs from ependymoma in adults where only 44.8% of cases occur in the brain and 55.2% occur in the spinal cord. Of the 2,098 pediatric patients identified, they were histologically identified as either Ependymoma, NOS (51.5%), or Anaplastic Ependymoma (47.5%). Comparatively, Anaplastic Ependymoma makes up only 9.7% of ependymomas in adult populations. Additionally, the majority of patients were Non-Hispanic (76.3%) and white (76.9%). Most patients were privately insured (58.0%) followed by those insured by Medicaid (33.1%). Pediatric ependymoma is primarily treated with surgical resection (95.7%). Conclusions: Compared to adult occurrences, pediatric cases of ependymoma are not only unique in the site that they affect but also in histology, with a higher proportion of anaplastic ependymoma. This NCDB analysis is the first to specifically analyze pediatric ependymoma and fills a gap in our understanding of how this cancer presents in children. The majority of ependymoma patients are non-Hispanic and White with a primary site occurring in the brain rather than in the spinal cord, consistent with literature. These findings emphasize the importance of a deeper understanding of the nature of this disorder. Future research should further explore the impact of demographic and socioeconomic factors on the treatments utilized, and overall survival of pediatric patients with ependymoma.
A preclinical study to evaluate the combination of azeliragon, an inhibitor of the receptor for advanced glycation endproducts (RAGE), with radiation therapy as a potential treatment of glioblastoma.
Authors: Ghosh Subhajit , Huang Jiayi , Hallahan Dennis , Marcus Stephen Garrett , Thotala Dinesh
Published: June 2023

e14056

Background: Systemic lymphopenia, which is independently associated with poor overall survival, is observed in approximately 30-50% of patients with glioblastoma (GBM) after chemoradiotherapy. We recently found that cranial irradiation of GBM tumors increases circulating myeloid-derived suppressor cells (MDSC) contributing to systemic lymphopenia. Additionally, we found that cranial radiation increases circulating levels of the RAGE ligands S100A8/9 and HMGB1, which have been reported to increase MDSC and their immunosuppressive effects through binding RAGE. We, therefore, hypothesized that targeting RAGE receptors on MDSC could prevent immunosuppression and improve survival in preclinical GBM models. Methods: We orthotopically implanted GBM cells (GL261 and CT2A) into immunocompetent C57BL6 mice. The GBM tumor-bearing mice were treated with five doses of fractionated radiation therapy (RT, 2 Gy/day for 5 consecutive days) to the whole head in combination with RAGE inhibitor azeliragon (0.1mg/mice/day i.p starting one day before RT for up to 10 days). We evaluated the immune cells in the tumor microenvironment (TME) and spleen at 14 days post-tumor implantation. We also evaluated the circulating immune cells and RAGE ligands (HMGB1 and S100A8/A9) in the plasma at 7, 14, and 21 days post-tumor implantation and monitored the mice for survival up to 60 days. Results: GBM tumor-bearing mice (GL261 & CT2A) treated with RT plus azeliragon had significantly improved survival when compared to RT alone or azeliragon alone. RT plus azeliragon significantly reduced the accumulation of granulocytic-MDSC (G-MDSC), monocytic-MDSC (M-MDSC), tumor-associated macrophages (TAM), and regulatory T cells (Treg), while increasing infiltrating CD8 T cells in the TME as compared to RT alone. RT alone significantly increased the accumulation of G-MDSC and M-MDSC in the spleen, which was significantly reduced with concurrent azeliragon. Concurrent administration of azeliragon with RT did not significantly affect the radiation-induced increase of circulating M-MDSC as well as plasma HMGB1 and S100A8/A9 concentration, though there was a modest reduction of circulating G-MDSC. Conclusions: Our study indicates that azeliragon, by blocking RAGE interaction with its ligands, helps to overcome the MDSC-mediated immunosuppression that occurs after RT. The combination of azeliragon with RT enhances survival in preclinical models. Clinical trials evaluating the safety and efficacy of azeliragon in combination with RT for newly diagnosed GBM are currently under development.
Hints for reclassification of meningiomas based on the fifth edition of WHO CNS.
Authors: Cheng Chuandong , Han Tiantian , Guo Didi , Kong Rongrong , Chen Siqi , Dong Yuwei , Wang Mengjuan , Ding Ran , Deng Wanglong , Bu Fanfeng , Wang Yuan
Published: June 2023

e14059

Background: Meningioma is the most common primary neoplasm of the central nervous system (CNS) in adults. Genetic variants ( NF2, AKT1, TRAF7 etc.) are strongly related to the subtypes of meningioma. TERT promoter mutation or homozygous CDKN2A and/or CDKN2B deletion are independent evidence for diagnosing WHO grade 3 meningioma according to 5th CNS WHO. Our study reclassifies meningiomas using a clinical and molecular real-world dataset. 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. Results: TERT promoter mutation or CDKN2A/B deletion were identified in 11% (n = 39) of patients ( TERT 5.2%, CDKN2A 8.1%, CDKN2B 8.6%). Of these cases, histologic grade information was available for 26 patients, 14(53.8%) of whom were reclassified as WHO grade 3 meningiomas, including four histologic grade 1 and ten histologic grade 2. There is a male preponderance in reclassified patients (56.4% vs. 40.0%, p < 0.05), meanwhile the age showed no significant difference between them (average age: 54 vs 50, p = 0.11). The most frequently co-mutated gene was NF2. The proportion of TERT promoter mutation or CDKN2A/B deletion in NF2-mutant tumors was similar to NF2-wildtype tumors (10% vs. 11%, p > 0.05). Conclusions: In our study, 11% of Chinese adult meningioma patients found TERT promoter mutation or CDKN2A/B deletion and showed a male preponderance, among 53.8% of whom were reclassified as meningiomas WHO grade 3. Overall, these data advance the understanding of the significance of molecular profiling in the classification of meningioma patients according to the 5th WHO CNS.
Outcomes of stereotactic radiosurgery in central nervous system lymphoma: A single institution experience.
Authors: Azad Farhan , Fekrmandi Fatemeh , Amin Mody , Goulenko Victor , Belal Ahmed , Plunkett Robert , Fabiano Andrew J. , Fenstermaker Robert Alan , Lipinski Lindsay J. , Torka Pallawi , Cortese Matthew Joseph , Hernandez-Ilizaliturri Francisco J. , Prasad Dheerendra
Published: June 2023

e14061

Background: Primary or systemic high-grade B-cell lymphoma with secondary central nervous system lymphoma (PCNSL or SCNSL) are currently treated with high-dose methotrexate (HD-MTx) based chemo-immunotherapy regimens with/without whole brain radiation therapy (WBRT). CNS relapse can occur in up to 50% of patients with PCNSL or SCNSL. WBRT has been used as a salvage therapy for those patients. However, long-term neurological toxicities significantly reduce its clinical benefit. Stereotactic radiosurgery (SRS) is the administration of a localized, high dose of ionizing radiation. Limited studies exist exploring SRS as a treatment modality in relapsed/refractory (r/r) PCNSL/SCNSL. Methods: We conducted a retrospective single-center study evaluating the clinical efficacy of SRS in r/r PCNSL/SCNSL. Demographic, clinical, pathological, and treatment characteristics were collected in 29 r/r PCNSL (N=17)/SCNSL (N=12) patients, age ≥ 18 years, who received SRS between 01/2000 and 01/2023. Progression-free survival (PFS) and overall survival (OS) were calculated and reported using Kaplan-Meier analyses and log-rank tests. Results: Baseline characteristics are summarized (Table). The median Karnofsky performance status and Charlson comorbidity index were 70 and 5 respectively. For patients with PCNSL (N=17), the most common prior chemotherapy regimen administered was rituximab (R) in combination with the DeAngelis regimen (N=12), followed by the MATRIX regimen (N=3). In patients with SCNSL, the most common systemic chemotherapy regimen used was R + CHOP (N=9). Few patients received temozolomide (N=2). 5/29 (17%) of patients received WBRT before SRS. The overall response rate (ORR) to SRS in r/r PCNSL was 60% (7 CR and 2 PR). The ORR in r/r SCNSL was 83% (7 CR and 3 PR). The median OS of the overall cohort was 7.0 months (95% CI 5.1-8.9), while the median PFS was 5.0 months (95% CI 1.2-8.7). For patients with PCNSL, the median OS was 10.0 months (95% CI 2.2-17.7), and only 7 months (95% CI 1.8-12.1) for patients with SCNSL. Prior WBRT was associated with worse survival outcomes. Of interest, WBRT was avoided in 24/24 patients (100%). Conclusions: Our data support that CNSL patients can benefit from SRS therapy, with acceptable OS and PFS. In addition, the disease control spared patients from WBRT and therefore, mitigated neurological complications associated with that modality. [Table: see text]
Ventriculoperitoneal shunt and performance status as prognostic factors of overall survival in a retrospective cohort of 78 adult patients with medulloblastoma.
Authors: Trejo-Rosales Raul Rogelio , De Jesus Hernandez Dulce Angelica , Merida Daniela Castro , Silva Godinez Juan Carlos , Otamendi-Lopez Andrea , Remolina Bonilla Yuly Andrea
Published: June 2023

e14062

Background: Adult medulloblastoma (AM) is a rare disease and represents 1 % of CNS tumors with an incidence of 0.6 per million per year. Usually arise in the cerebellar hemisphere or dorsal brainsteam. Four molecular subgroups are widely recognized and SHH subgroup are common in AM. Treatment options are usually extrapolated from pediatrics experience, and involve surgical resection followed by radiotherapy +/- chemotherapy. Methods: We conducted a retrospective cohort study in patients with medulloblastoma aged ≥18 years at a tertiary institution in Mexico City. We aim to describe clinical and treatment patterns predicting OS and PFS in an adult cohort of medulloblastomas. Kaplan Meier and Log-rank methods were used for survival analysis. Cox proportional hazard model was used for multivariate analysis. Results: Between 2010 and 2022, 78 patients met the criteria for this study. The median age was 28 years (range 18-62) and 64.1% were men. A total of 75.6% had ECOG 0-1. The desmoplastic was the most frequent histologic variant (35.9%). Surgical resection was performed in 93.6% with R0 resection in 49.3% (n=36), while 76.9% (n=61) underwent ventriculoperitoneal shunt (VPS). A total of 70 pts (89.7%) received adjuvant radiotherapy (RT), and the median time to initiation was 18 weeks. Adjuvant and concurrent chemotherapy were received in 53.8% and 12.8%, respectively. One-third of patients did not receive chemotherapy. Vincristine, cisplatin, and cyclophosphamide was the most common combination chemotherapy regimen (28.5%). PFS and OS in the entire cohort were 27.9 months (mo) (95% CI 9.9-45.9) and 124.3 mo (95% CI 52.8-59.8), respectively. OS in patients with ECOG 0-1 was better with 144.8 mo compared with 51.5 mo for ECOG 2-3 (p<0.001). Patients receiving adjuvant RT survived significantly longer (124.3 mo) than patients without radiation (18.8 mo). Other factors associated with survival were time to RT initiation ≤18 weeks vs >18 weeks (not reached vs 59.1 mo, p=0.018) and VPS insertion (144.8 mo vs 46.5 mo, p=0.023). Multivariate analysis identified performance status such as ECOG 2-3 (HR 2.93; 95% CI 1.3-6.6, p=0.009) and VPS (HR 0.39; 95% CI 0.16-0.93, p=0.034) as independent prognostic factors for OS. Conclusions: in this large cohort of Adult Medulloblastoma, we identified ventriculoperitoneal shunt and performance status as the most important factors related with better survival outcomes.
Real world data about stupp platform in the treatment of glioblastoma in a single center of Colombia.
Authors: Cantor Rizo Erick Andres , Segovia Javier , Pino Luis Eduardo , Vargas Henry , Triana Ivan , Murillo Silva John Alejandro , Ospina Serrano Aylen Vanessa
Published: June 2023

e14065

Background: Glioblastoma cancer is a disease with high mortality reported worldwide. However, in Colombia and Latin America there is a large gap in terms of the information available regarding the characteristics and survival of these patients. Methods: This is an observational, descriptive study of a cohort of patients with glioblastoma cancer who initiated medical treatment at Fundación Santa Fe de Bogotá, a high complexity hospital. We analyzed clinical characteristics, IDH mutation, histology, treatments, progression free survival (PFS), overall survival (OSm) and treatment related complications. We use Kaplan Meier as survival statistic. Results: Twenty patients were included during the 48 months. The average age was 62 years. 65% males, 35% female. IDH mutation detection was performed in 100% of patients, and IDH1 was positive in 20% of the population. Regarding the anatomy location occipital lobe 5%, temporal 20%, parietal 5%, frontal 35%, other locations 35%, ECOG 0-1 were the 100%. Time from start to stupp platform after surgery was 6.1 weeks. All patients received the surgical treatment scheme, later stupp platform followed by temozolamide. In the survival analysis, 15% of patients died during follow-up and 35% progressed to first line. The median overall survival (OSm) 19m, and Progression-free survival (PFS) 14m for the global population. Adjusting survival models for confounding variables, in males the OSm 19 and 15.6m in females. The PDF 15,6m males and 11.8m in females. The OSm in patients with IDH negative 20m, and in the group with IDH1 mutated the OSm has not been reached to 18m of follow-up. Conclusions: Our cohort of patients is similar to the literature reported worldwide, gender may be a predictor of risk. We have good survival times with the stupp platform, rapid access to treatment may be a factor in favor of our good outcomes.
Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in healthy male subjects.
Authors: Vogg Barbara , Poetzl Johann , El Galta Rachid , Fuhr Rainard , Schwebig Arnd , Sekhar Susmit
Published: June 2023

e14500

Background: Denosumab is a human monoclonal antibody that binds to RANKL, preventing activation of its receptor RANK on the surface of osteoclasts and inhibiting osteoclastic bone resorption. This study was conducted to support demonstration of biosimilarity by evaluating similarity in pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between GP2411, a proposed Sandoz denosumab biosimilar, and reference denosumab in healthy male subjects. Methods: This double-blind, three-arm, parallel-group, PK and PD study was conducted at two centres in Germany. Participants were randomised (1:1:1) to receive a single 35 mg s.c. dose of either GP2411, EU-authorised reference denosumab, or US-licensed reference denosumab and were followed-up for 39 weeks. A sub-therapeutic dose was chosen since it is more sensitive than therapeutic doses to detect potential PK and PD differences; PK and PD similarity established at the 35 mg dose supports extrapolation to therapeutic doses. The study enrolled 502 healthy male subjects, aged 28–65 years, with a body weight range of 50–90 kg. PK endpoints included the area under the serum concentration-time curve measured from the time of dosing and extrapolated to infinity (AUCinf), or to the last measurable concentration (AUClast), and maximum observed serum concentration (Cmax). PD endpoints were the area under the effect-time curve (AUEC) of the percentage change from baseline (%CfB) in serum carboxy-terminal crosslinked telopeptide of type I collagen (CTX), and CTX and procollagen I N-terminal propeptide (PINP) serum concentration per visit. Results: Overall, 499 healthy volunteers received one of the three treatments. PK and PD similarity was demonstrated between GP2411 and its reference biologic (EU-authorised and US-licensed), as the 90% CIs and 95% CIs of the geometric mean ratios for PK and PD parameters were fully contained within the prespecified equivalence margins [0.80, 1.25]. Changes from baseline to Week 39 in serum concentrations of CTX and PINP were similar between groups. Conclusions: PK and PD similarity between GP2411, a proposed Sandoz denosumab biosimilar, and reference denosumab were demonstrated in healthy male subjects. [Table: see text]
Characterizing the tumor selectivity of oncolytic adenovirus ICVB-1042: Analysis of S-phase induction, viral replication, and cytolytic activity in human primary normal cell types.
Authors: Pokrass Michael , Rosenthal Peter , Messinger Joshua , Rodriguez Ruben , Nowyhed Heba
Published: June 2023

e14503

Background: Adenoviral-based oncolytic virus (OV) therapeutics include mutations that enable activity in tumor cells and limit toxicity in normal cells. These tumor selectivity approaches often involve mutating viral E1A function or expression; however, such modifications allow viral activity in normal cells or limit anti-tumor potency. ICVB-1042 was engineered with dual modifications in E1A and E4orf6/7, resulting in superior tumor selectivity that does not compromise lytic potency in tumor cells. This improved tumor selective virus minimizes off-tumor activity and promotes robust tumor lysis. Methods: ICVB-1042 was compared to viruses with wildtype E1A and E4orf6/7 and a clinically tested virus with an E1A mutation (ICVB-2006). Viral function and killing were assessed in primary normal human renal (HRE) and bronchial (BrE) epithelial cells in the presence of the inhibitor palbociclib to pharmacologically block S-phase entry via host cell signaling. HRE and BrE were infected with virus and evaluated for indicators of viral toxicity in normal cells. Viral replication was quantified by droplet digital polymerase chain reaction (ddPCR); cell lysis was quantified by WST-1 assay. An S-phase induction assay was developed using an mCherry-Geminin reporter that allows imaging-based quantification of viral-dependent entry to S-phase. Viral activity in cells was compared with and without the CDK4/6 inhibitor using a viral-encoded fluorescent reporter to determine the requirement for host cell proliferation on viral function. Results: ICVB-1042 demonstrated superior protection in normal cells to comparator ICVB-2006 and viruses lacking tumor selectivity modifications. Palbociclib steeply reduced viral reporter gene expression (63-88% reduction), viral replication ( > 10-fold reduction), and cytolytic activity of ICVB-1042, while non-selective viruses were unaffected by this treatment. Non-selective virus infection resulted in 3.3- to 6.1-fold higher levels of S-phase entry compared to ICVB-1042. ICVB-2006 infection resembled non-selective viruses at the level of S-phase induction (3.1- to 3.3-fold above ICVB-1042) and viral reporter gene expression was modestly inhibited by palbociclib (12-31% reduction). Conclusions: The improved tumor selectivity of ICVB-1042 results in protection of normal, non-proliferative cells from viral-mediated toxicity. The conventional approach of ICVB-2006 with a single E1A mutation leaves viral replication and cell death in normal human cells mostly intact. Together, these observations support that ICVB-1042 presents normal cell protection and reduced toxicity risks associated with OV therapy.
Development of a CCR8 monoclonal antibody to block CCR8 signaling and to abolish the immunosuppressive function of Treg for the treatment of cancers.
Authors: Fan Guohuang , Wang JianFei , Wang Zhilong , Zhang Yong , Zhang Yuanyuan , Tian Binle
Published: June 2023

e14506

Background: The tumor microenvironment (TME) contains regulatory T (Treg) cells, which play a critical role in immunosuppression and are thus an attractive target for cancer therapy. The ideal approach would be to inhibit Tregs within tumors while sparing those in peripheral and normal tissues. Tumor-associated Tregs express the chemokine receptor CCR8, which is involved in the induction, expansion, migration, and immunosuppression of Tregs, making targeted inhibition of CCR8 signaling a potential therapeutic strategy against cancer. Methods: We have developed IPG0521, a monoclonal antibody antagonist of CCR8, and characterized its properties, including signaling blocking, chemotaxis, species cross-reactivity, anti-tumor efficacy, and synergistic antitumor effect with PD1 antibody. Single-cell RNA sequencing with CD45+ cells isolated from tumors treated with or without IPG0521 was also employed for profiling the mechanism of the antitumor effect of IPG0521 in the murine H22 cancer model. Results: IPG0521 inhibits receptor-mediated signaling and chemotaxis in Treg cells with a single-digit nanomolar IC50. It is cross-reactive in five species: mouse, rat, dog, monkey, and human. IPG0521 has shown excellent anti-tumor efficacy in several murine syngeneic cancer models, and its anti-tumor effect is enhanced when combined with a PD-1 antibody. Its sustained anti-tumor efficacy has been demonstrated in the murine H22 cancer model via even withdrawing the antibody during the study. The results of deep single-cell RNA sequencing on tumor-infiltrating lymphocytes (TILs) showed that the transcriptional profiles of these Treg cells could be distinguished into three distinct subsets based on molecular, functional, and immunosuppressive properties. These subsets were defined as the Treg_Foxp3 high subset, which exhibited low immunosuppression, the Treg_Foxp3 mild subset, which demonstrated mild immunosuppression, and the Treg_Foxp3 low subset, which had high proliferation. IPG0521 treatment resulted in a significant increase in the Treg_ Foxp3 high subset and a significant decrease in the Treg _ Foxp3 mild subset while no change in the Treg_ Foxp3 low subset, indicating a reduction in Treg immunosuppression. This change in Treg cells also altered the composition of other immune cells, including a significant increase in neutrophils and natural killer (NK) cells, which ultimately inhibited tumor growth. Conclusions: IPG0521 has potent anti-tumor effects in multiple tumor types, including lung, liver, and breast cancers, in both syngeneic and immune-humanized mouse models. It inhibits Tregs immunosuppression and activates CD8+ T cells to achieve its anti-tumor effects. These results support the development of IPG0521, which is currently under IND filing, as a novel therapeutic agent for the treatment of cancers.
In vivo anti-tumor effects of XON7 in association with ICIs.
Authors: Ciron Carine , Duvaux Odile , Shneiker Françoise
Published: June 2023

e14520

Background: The advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm for multiple cancer types. This remarkable shift has been driven in large part by unprecedented durability that is characteristic of ICIs responsiveness. However, ICIs promote tumor cell immune escape; indeed, the response rate to single agent PD-1 blockade in unselected patients ranges from 40 to 70% in some diseases, while the response rates in most other approved diseases is limited to 10–25%. These observations support the need to strengthen immunotherapy and bring additional benefits for patients. XON7, is a glyco-humanized polyclonal antibody (GH-pAb) targeting multiple tumor antigens and active in vitro and in vivo in several solid tumors and hematological malignancies. Methods: A human lung carcinoma chorio-allantoic membrane (CAM) model was used to evaluate the efficacy of XON7 + anti PD-1 treatment. Fertilized white Leghorn eggs were incubated until Day 9, then inoculated in the upper CAM with 1.106 H460 cells. Treatments were administrated at E10, E12, E14, E15 and E17. Two groups were included: control group (n=20) received a non-immune GH-pAb + anti-PD-1 (10 mg/kg + 2,5 mg/kg respectively); treated group (n=20) received XON7 and anti-PD-1 at the same doses. Upper CAM, lower CAM and brain were collected from the embryos at E18. Tumor growth was evaluated by tumor weight using one-way ANOVA. Metastasis were quantified by qPCR for Alu sequences. Immune cell infiltration was analyzed by RT-qPCR with specific primers for chicken CD3, CD4 and CD8 sequences, with GAPDH as reference gene expression. Results: Significant reduction in tumor growth (~30%, p=0.02) and metastasis (>90%, p=0.001) was observed in both the brain and the lower CAM in the XON7+ICI group compared to control group. No differences in lymphocyte infiltrates (CD3, CD4, and CD8) were observed between groups. However, a significant increase in the M1/M2 ratio was observed in the XON7 + anti-PD-1 group over control. No toxicity from the treatment appeared in this model. Conclusions: In vivo data showed a significant increase of response rate and decrease of metastasis when XON7 is associated with anti PD-1. Combination of GH-pAb with ICI could constitute an immunotherapy combination likely to overcome resistance to anti-PD1.
The SPEARHEAD-1 trial of afamitresgene autoleucel (afami-cel [formerly ADP-A2M4]): Pooled analysis of cytokine release syndrome across cohorts in patients with advanced synovial sarcoma.
Authors: D'Angelo Sandra P. , Ganjoo Kristen N. , Blay Jean-Yves , Valverde Claudia , Araujo Dejka M. , Abdul Razak Albiruni Ryan , Le Cesne Axel , Schuetze Scott , Wagner Michael J , Attia Steven , Forcade Edouard , Druta Mihaela , Pollack Seth , Bai Jane , Lunt Colin , Sun Amy , Yule Murray , McAlpine Cheryl , Williams Dennis , Van Tine Brian Andrew
Published: June 2023

e14531

Background: Afami-cel is an autologous, T-cell receptor T-cell therapy engineered to target melanoma-associated antigen A4 (MAGE-A4) in human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors. SPEARHEAD-1 (NCT04044768) is a Phase 2, two cohort, open-label trial to evaluate the efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma. Here we report data on cytokine release syndrome (CRS) in the pts with advanced synovial sarcoma treated with afami-cel across Cohort 1 and Cohort 2. Methods: Eligible pts had advanced synovial sarcoma and were HLA-A*02 positive with MAGE-A4–positive tumors. Pts received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. Tocilizumab administration was permitted for Grade 1 CRS if symptoms persisted for ≥ 24 hours or if the pt had co-morbidities, and for Grade ≥2 CRS. Results: As of August 29, 2022, 72 pts with synovial sarcoma received afami-cel (n = 44 Cohort 1; n = 28 Cohort 2). Afami-cel dose range was 1.92–10.00×109 transduced T-cells. The median age was 39.5 years (range: 16–73 years), 47.2% of pts were female, 88.3% of pts were white, and tumor MAGE-A4 expression H-score was 244.5 (range: 66–300). CRS occurred in 72.2% of the pts with synovial sarcoma receiving afami-cel, including Grade 1 in 50% (36/72), Grade 2 in 20.8% (15/72), and Grade 3 in 1.4% (1/72) of pts as per American Society for Transplantation and Cellular Therapy grading. The median time to onset was 2.5 days (range: 1–5 days), and the median time to resolution was 3 days (range: 1 to 14 days). Twenty-seven of 72 (37.5%) pts received at least one dose of tocilizumab. Consistent with expectations, higher serum IL-6 levels were associated with CRS events and the indicated use of tocilizumab for management. RECIST v1.1 responses were observed in pts with and without CRS. Correlation of clinical factors and CRS with response will be presented. Conclusions: CRS was common after afami-cel administration but was mostly low grade. Administration of tocilizumab in SPEARHEAD-1 was effective in the management of CRS. Clinical trial information: NCT04044768 .