bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seizures as treatment-emergent adverse events during glioblastoma clinical trials.
Authors: Dillman Robert O. 
Published: June 2022

e14018 Background: Seizures are not an uncommon presenting symptom of glioblastoma (GBM), and may occur following surgery for GBM. Such seizures typically can be controlled with anti-epileptics, and the risk of seizures seems to decrease after concurrent radiation therapy and temozolomide chemotherapy (RT/TMZ). However, the risk of seizures theoretically might be increased in association with a therapeutic intervention designed to enhance local inflammation at the GBM site. 33% of patients experienced one or more seizures as a treatment-emergent-adverse-event (TEAE) during a phase II clinical trial of AV-GBM-1, patient-specific dendritic cell vaccines that consist of autologous dendritic cells loaded with autologous tumor associated antigens derived from a short-term culture of self-renewing tumor cells, that were injected subcutaneously for up to six months after recovery following concurrent RT/TMZ (Bota DA et al. 2021 Society for Immunotherapy of Cancer (SITC) late-breaking abstract #952, 2021 Society of Neuro-Oncology abstract #CTIM-33). A literature search was conducted to determine reported rates of seizures as TEAE in primary GBM patients in clinical trials. Methods: Phase III trials of systemic treatment of primary GBM, and published during 2005 to 2021, were identified by searches of clinicaltrials.gov and PubMed. Published reports were reviewed for data describing the frequency of seizures reported as TEAE in text and/or summary tables. Only trials that had at least 50 patients in a standard treatment arm of surgical resection, RT/TMZ and maintenance TMZ were included. Chi square test was used to compare proportions of patients experiencing seizures in these trials. Results: Eight such randomized trials were identified. Five trials did not mention seizures as TEAE. One trial provided data only for grade 3 and 4 events: 13/229 (5.7%). The other two trials reported all seizures regardless of grade, but were limited to patient populations with O6-methylguanine-DNA-methyltransferase promoter methylation in one, and epidermal growth factor receptor amplification in the other. The rates of seizures in those two trials were much lower than the 19/57 (33.0%) reported with AV-GBM-1: 28/258 (10.9%, p < 0.0001), and 69/372 (15.4%, p = 0.0136). Conclusions: The frequency of seizures that occur in GBM patients receiving standard RT/TMZ is not well-documented in publications of large, randomized trials. AV-GBM-1 may be associated with a higher rate of seizures because of treatment-induced inflammation at the tumor site, but a randomized trial would be needed to determine this.
Anlotinib plus radiotherapy-temozolomide for newly diagnosed glioblastoma: A prospective, multicenter phase II study.
Authors: Lai Shuzhen , Chen Yuan yuan Yuan , Li Peijing , Jiang Fagui , Liu Xiaohui , Tao Changjuan , Huang Jing , Tang Yiqiang , Liu Zhigang , Shen Guoping , Li Chaoming , Xie Tieming , Lu Fangxiao , Liu Guihong 
Published: June 2022

e14020 Background: Concurrent radiotherapy and temozolomide (TMZ) followed by adjuvant TMZ (STUPP regimen) is the standard therapy for newly diagnosed glioblastoma after resection, however, the progression-free survival (PFS) was only about 7 months (m) and the overall survival (OS) was less than 17m. This study aims to assess the efficacy and safety of adding anlotinib, a multitarget tyrosine kinase inhibitor, to the STUPP regimen for newly diagnosed glioblastoma. Methods: This was a prospective, sing-arm, multicenter, phase II study (NCT04119674). Eligible patients (pts) were diagnosed with newly diagnosed GBM and had undergone surgery within 6 weeks before enrollment. Previous exposure to other therapies was not permitted. Other key inclusion criteria included 18 to 75 years old, Karnofsky performance status ≥ 60 %, had at least one measurable lesion according to RANO criteria, and adequate bone marrow, hepatic, and renal functions. All pts received radiotherapy (54̃60 Gy administered as 1.8-2.0 Gy fractions, 5 days per week) for 6 weeks, with concurrent oral TMZ (75 mg/m2 QD) and anlotinib (8 mg QD, d1̃d14 per 3 weeks). After a 28-day treatment break, adjuvant therapy was started with six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) ，and followed by anlotinib monotherapy until disease progression or intolerable toxicities. The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were recorded according to CTCAE 5.0. Results: From January 2019 to February 2021, 33 pts (17 males and 16 females) were enrolled from 7 hospitals in China. The median age was 52 (range: 32, 69). At the data cutoff date on January 25th, 2022, all pts had completed the concurrent treatment and 30 pts (90.0%) completed the 6 cycles of adjuvant treatment. The median treatment duration of anlotinib was 16 cycles. At the data cutoff date, 21 patients experienced disease progression and 17 pts were dead. The median PFS was 10.9m (95% CI, 6.6-15.2) and the median OS reached 18.7m (95% CI, 15.0-22.4). The PFS at 1 year was 45.5% and OS at 1 year was 72.7%. No grade 3 or worse AEs were observed during the concurrent phase and anlotinb maintenance phase. Three pts (9.1%) had grade 3 or 4 thrombocytopenia and 1 pts (3.0%) had grade 3 vomiting during the course of adjuvant therapy. Conclusions: This is the first study to explore the feasibility of adding anlotinib to the standard treatment for newly diagnosed GBM. The efficacy was impressive in that the median OS had exceeded 18m and the safety profile was favorable. The positive-controlled study was ongoing. Clinical trial information: NCT04119674.
Using variant allelic fraction of driver mutations to determine the reliability of MGMT promoter methylation testing in adult-type diffuse gliomas.
Authors: McCord Matthew , Jamshidi Pouya , Bell Burdett Kirsten Bell , Jennings Lawrence , Horbinski Craig M. 
Published: June 2022

e14034 Background: Methylation of the O6-methylguanine-DNA methyltransferase ( MGMT) promoter predicts response to temozolomide (TMZ) in adult-type diffuse gliomas. MGMT testing is thus standard practice. However, accurate results depend on adequate tumor cellularity in the analyzed sample. If the sample contains too many admixed nonneoplastic cells (which are consistently MGMT unmethylated), a false-negative result may be generated. Currently, ̃70% tumor cells are considered the minimum for reliable testing, but that is based on visual estimation by light microscopy; such estimation varies between observers and is often inaccurate. Since next-generation sequencing (NGS) is also frequently done on adult-type diffuse gliomas, and such tumors usually have heterozygous driver mutations known to be present in nearly 100% of tumor cells (IDH mutations in astrocytomas and oligodendrogliomas; TERT promoter mutations in ̃85% of IDH wild-type GBM), we sought to determine whether the variant allelic fraction (VAF) of these mutations could improve quality assurance in MGMT promoter methylation testing. Methods: We used an in-house cohort of 175 WHO gliomas (112 IDHwt, TERTmut GBM, 34 WHO grade 2-4 IDHmut astrocytomas, 29 WHO grade 2-3 IDHmut oligodendrogliomas), all with MGMT pyrosequencing and NGS data obtained from the same tissue blocks. Gliomas with average 10% methylation across all four CpG sites in the MGMT promoter were considered positive, as per standard cutoffs for that assay. Results: Overall, there was a positive correlation between driver VAF and amount of MGMT promoter methylation (slope = 0.25, R2= 0.33, P = 0.016). The largest dropoff in average methylation was when VAF was below 13% (7.4% average CpG methylation when VAF < 13% vs. 19.0% when VAF≥13%, P= 0.029). Based on our prior published study (PMID: 33830235), 36.5% of IDHwt GBMs, 86.7% of IDHmut astrocytomas, and 98.6% of IDHmut oligodendrogliomas should have MGMT promoter methylation. Among our GBMs, only 1/7 (14.0%) below a TERT mutant VAF of 13% reached the cutoff for MGMT promoter methylation, whereas 39/105 (37.0%) of GBMs VAF≥13% did. However, this did not reach statistical significance, likely because our cohort was underpowered for GBMs with TERTmut VAF < 13%. Among 34 IDHmut astrocytomas, only 1 had a VAF below 13%, and was reported as MGMT promoter unmethylated; all others had VAF between 21-56%, and showed consistent rates of MGMT methylation positivity across that entire range. All 29 oligodendrogliomas had VAFs of at least 26%; 2/29 were MGMT-negative, and both had VAFs at or above 36%. Conclusions: Additional cases are being prospectively collected to boost statistical power. Still, our existing data suggest that, when driver mutation VAF falls below ̃13% (i.e., tumor cellularity ̃26%), the risk of false-negative MGMT methylation results increases, and caution is warranted in such cases.
Efficacy of Gemcitabine in recurrent meningioma: A phase II study.
Authors: Shah Devanshee , Menon Nandini Sharrel , Puranik Ameya , Choudhary Amit , Patil Vijay Maruti , Pathak Shruti , Peelay Zoya 
Published: June 2022

e14044 Background: Systemic therapy has a limited role in meningiomas. There is in-vivo and in-vitro data that gemcitabine can potentially be useful in meningiomas. We did a phase II study with the primary objective of studying the 6-month progression-free survival (PFS) of gemcitabine in meningiomas. Methods: This was a single-arm prospective phase II study. Adult patients with recurrent meningiomas who were not eligible for local therapies with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 with normal organ and marrow function were included in this study. Patients who had received any chemotherapy within the last three weeks or on any other investigational agents were excluded. All patients received gemcitabine 1000 mg/m2 administered intravenously over 30 minutes on day 1, day 8 and day 15 every 4 weeks until disease progression or development of intolerable side effects. The response was assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. The adverse events were recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The primary objective of this study was to assess the 6-months progression-free survival (PFS). The 6-months progression-free survival (PFS) of 50% or more was considered sufficient to warrant further studies. Results: Nine patients were recruited in this study. The median age of the patient was 56 years(24-73). The m: f ratio was 2:3. All patients had undergone previous surgeries and 8 patients had undergone previous radiotherapy. The median number of cycles of gemcitabine was 3. Any grade toxicity was observed in all patients. Grade 3 and above adverse events were not observed. The two commonest adverse events noted were anaemia in 7 (77.8%) patients and vomiting in 2 (22.2) patients. The best response was stable disease (SD) in 3 patients (33.4%) and progressive disease (PD) in 6 (66.6%) patients. At a median follow up of 18.8 months, the 6-months progression-free survival (PFS) was 33.3% (95%CI 7.8-62.3). The 1-year overall survival (OS) was 66.7 % (95%CI 28.2-87.8). Conclusions: Gemcitabine failed to meet the prespecified endpoint of 6-month PFS and does not warrant any further investigation in this setting. Clinical trial information: CTRI/2019/02/017499.
A novel humanized antibody targeting CD39 that enhances anti-tumor immunity and the efficacy of cancer immunotherapy.
Authors: Ban Haruka , Obonai Toshifumi , Mishima Yuji , Matsumoto Noriko , Mie Motoya , Nakamura Norihiro 
Published: June 2022

e14508 Background: Immunotherapy using immune-checkpoint inhibitors (ICIs) has shown remarkable clinical efficacy in patients with cancer. However, it is crucial to utilize appropriate combination of immunotherapy for patient condition, as most patients do not benefit or sustain responses of immunotherapy. We focused on CD39 that is highly expressed in some tumors and tumor infiltrating immune cells (e.g. exhausted T cells and Tregs) as a target for cancer immunotherapy. CD39 is an ectoenzyme that converts extracellular ATP to immunosuppressive adenosine. Since the ATP-adenosine pathway is a key modulator of innate and adaptive immunity within the tumor microenvironment (TME), we presume that anti-CD39 antibodies suppress the production of adenosine and limit the immunosuppressive state in TMEs. Methods: Anti-human CD39 antibodies were screened by sorting B cells of mice immunized with human CD39 protein. The obtained clones that inhibit enzyme activity of CD39 were humanized on IgG1 and IgG4. PBMC were used in proliferation and functional assays. The anti-tumor effect was investigated with mouse xenograft model. Results: Analyzing gene expression profiles from TCGA data, high CD39 expression is associated with a poor prognosis in several cancers. There was a strong correlation between them in multiple myeloma treated with chemotherapies. The expression of CD39 was upregulated in some cancer cell lines treated with chemotherapeutic agents. A novel humanized anti-CD39 antibody, BP1202, which has a high affinity for the recombinant CD39 protein (KD: 481 pM) and inhibits the enzyme activity of CD39 expressed on a cancer cell line (IC50: 1 nM) and human Tregs. The antibody showed a high potency to enhance T cell activity including their proliferation, cytokine production, and cytotoxicity against a cancer cell line. We examined the anti-tumor effect of BP1202 in vivo using tumor-bearing mice and found that the combination treatment of BP1202 with chemotherapeutic agents significantly reduced tumor volume. Conclusions: We developed a new humanized antibody that enhances anti-tumor immunity by inhibiting CD39 expressed on exhausted T cells and intra-tumor T cells. These data suggest the scientific rationale for the clinical development of BP1202 and their use in combination with ICIs, with ATP-adenosine pathway inhibitors, and with chemotherapies. BP1202 is currently being developed as a new antibody agent for cancer immunotherapy.
Engineered, fully human nanobody-based CAR T cells have enhanced antitumor activity against hepatocellular carcinoma in preclinical models.
Authors: Kolluri Aarti , Li Dan , Li Nan , Ho Mitchell 
Published: June 2022

e14512 Background: Glypican 3 (GPC3), a cell surface protein associated with early development, is an established biomarker of hepatocellular carcinoma (HCC). In a vast compendium of work, HN3, a human GPC3 nanobody (VH) isolated from a phage library, was shown to abrogate HCC tumors and block the distally located Wnt binding domain of GPC3. To date, it remains challenging how to precisely engineer CAR T cells for improved efficacy in solid tumors. In the context of hepatocellular carcinoma, we determined how hinges and transmembrane portions of varying structures and sizes affect CAR T cell function. Here, we show how rationally designed, engineered Chimeric Antigen Receptor (CAR) T cells containing HN3, demonstrate enhanced CAR T activity in HCC. Methods: We generated and compared multiple permutations of GPC3 targeted CAR T cells containing HN3, CD8, CD28, IgG4 and Fc domains. Incorporation of HN3, into multiple CAR formats yielded nine constructs, which were screened for antigen-specific and antigen-independent signaling using a luciferase reporter system in Hep3B, Huh7 and HepG2 cell lines. For in vivo assessment, immunodeficient NSG mice were intraperitonially injected with Hep3B or Huh7 cells and treated with a single dose (5 or 15 million) of engineered HN3 CAR T cells. Blood was collected at 2, 4 and 5 weeks to assess proliferation, T cell subtypes and exhaustion. Results: In vitro, the HN3-IgG4H-CD28TM CAR T cells induced high specificity and cytotoxic activity. HN3-IgG4H-CD28TM CAR T cells markedly improved HN3 cell killing activity by 30-40% in low (1.6:1) and high (25:1) effector to target ratios. Similarly, in vivo, in a high antigen environment, two determinative changes in the hinge region and transmembrane domains led to complete tumor eradication in immunodeficient mice bearing HCC tumors within 7-10 days. Moreover, HN3-IgG4H-CD28TM CAR T cells maintained specific tumor killing and averted exhaustion by producing a clear T cell response signature of enriched cytotoxic-memory (Temra) CD8+ along with a subset of naïve T cells. Conclusions: Engineered nanobody based CAR T cells containing the appropriate hinge and transmembrane domains can lead to determinative T cell signaling capable of inducing swift and durable eradication of HCC tumors. Altogether, we show that engineered HN3 CAR T cell therapy demonstrates strong potential for treatment of aggressive HCCs enabled by Wnt dysregulation.
Baseline endogenous corticosteroid as a biomarker for predicting response to immune checkpoint blockade in patients with metastatic cancer.
Authors: Wang Jun , Cui Yu , Guan Yaping , Yin Beibei , Xie Qi 
Published: June 2022

e14588 Background: Previous studies indicate that exogenous use of corticosteroids affects immune checkpoint inhibitor (ICI) efficacy comparing patients receiving corticosteroids versus no corticosteroids. However, there is a paucity of clinical data evaluating the direct effect of endogenous corticosteroids on ICI efficacy for cancer patients with immune checkpoint blockade. Methods: We retrospectively reviewed patients with advanced cancer who were treated with PD-1 inhibitor alone or combination therapy in a single center between December 2019 and January 2022. Serum corticosteroid levels (8:00 AM) were routinely measured before ICI treatment. The effects of serum corticosteroids on objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were analyzed. Propensity score matching (PSM) analysis was performed to match the characteristics of the high and low serum corticosteroid groups. Results: A total of 144 patients were included in this retrospective cohort study. The median age was 62.5 years and 71.5% was male. Overall, ORR was 20.1%, and median OS and PFS were 22.2 and 4.9 months, respectively. Patients with low corticosteroid levels (n = 64) had a significantly improved ORR compared to those with high corticosteroid levels (n = 80) (34.4% vs 8.8%; p < 0.001). The increased corticosteroid level was significantly associated with reduced OS ( p < 0.001) and PFS ( p = 0.025) for all patients and those with non-small cell lung cancer regarding OS ( p = 0.004). Moreover, statistically significant differences regarding OS ( p = 0.017) were also detected after PSM. In a multivariable model, the corticosteroid level was identified as an independent indicator for predicting OS ( p = 0.001) and PFS ( p = 0.006). Conclusions: Endogenous corticosteroid can predict efficacy and prognosis for advanced cancer patients with immune checkpoint blockade. Baseline evaluation of baseline corticosteroids should be considered before ICI initiation. Further prospective clinical trials designed to validate the predictive role of endogenous corticosteroid are warranted.
Risk and predictors of ipilimumab-associated cardiac adverse events among patients treated for melanoma: A national cohort analysis.
Authors: Labban Muhieddine , Adib Elio , Langbein Bjoern , Chen Xi , Nguyen David-Dan , Cole Alexander P , Lipsitz Stuart R. , Sun Maxine , Trinh Quoc-Dien 
Published: June 2022

e14592 Background: Ipilimumab is a CTLA-4 inhibitor widely used to treat advanced melanoma. While ipilimumab-induced cardiac immune-related adverse events (irAE) have been reported, there is a paucity of data from large cohorts. We investigated the risk and predictors of ipilimumab-associated cardiac irAE in a national cohort of patients with cutaneous melanoma. Methods: Using SEER-Medicare linked data, we compared the risk of cardiac irAE between patients treated with ipilimumab with or without concomitant treatment for cutaneous melanoma and controls not treated with ipilimumab following a primary diagnosis of cutaneous melanoma. We excluded patients ≤65 years and patients with cardiac comorbidities diagnosed within one year prior to the initiation of melanoma treatment. The primary endpoint was the incidence of at least one cardiac irAE after ipilimumab initiation including acute pericarditis, myocarditis, cardiomyopathy, conduction disorders, cardiac dysthymias, acute heart failure, and takotsubo syndrome. To estimate the risk of cardiac irAE, we conducted a multivariable competing-risk analysis adjusting for death of any cause within one year of treatment as a competing event. Then, we constructed a stepwise logistic regression to assess the predictors of having at least one cardiac irAE within one year of ipilimumab initiation. Subgroup analysis was conducted among patients who received ipilimumab only. The models were adjusted for patient demographics, disease stage, Charlson comorbidity index (CCI), history of hypertension, autoimmune disease, end stage renal disease (ESRD), chronic anticoagulant, and steroid use. Results: The cohort included 715 patients treated with ipilimumab and 22,070 controls. In the ipilimumab arm, 23.4% had metastatic disease, 9.5% had a history of autoimmune disease, and 2.2% had CCI≥2. The incidence rates of cardiac irAE among patients who received ipilimumab and among the control group were 23.3 and 13.6 per 1,000 person-years, respectively. We found that patients who received ipilimumab had a higher risk of cardiac irAE compared to controls (adjusted hazard ratio 1.87; 95%CI 1.50-2.32; p < 0.001). In addition to ipilimumab treatment, other predictors of cardiac irAE included male gender, older age, patients with metastatic disease, history of autoimmune disease, hypertension, ESRD, anticoagulant use, and CCI≥2. The predictors of cardiac irAE were also consistent in the subgroup analysis of patients who received ipilimumab only. Conclusions: Patients who received ipilimumab with or without concomitant treatment for cutaneous melanoma had a higher risk for cardiac irAE. Predictors of cardiac irAE help tailor therapy according to patients’ risk profiles.