bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron surveillance and management in gastrointestinal oncology patients: A national survey of physician practice.
Authors: Brezden Christine , Remtulla Tharani Alliya , Hrycyshyn Adriyan , Abbruzzino Alexandria , Smith Janet , Kachura Jacob , Sholzberg Michelle , Mosko Jeff , Chadi Sami A. , Burkes Ronald L. 
Published: June 2022

e13644 Background: In 2018, there were an estimated 4.8 million new cases of gastrointestinal (GI) cancers worldwide and 3.4 million related deaths. Iron deficiency (ID) is a frequent complication of GI malignancy that eventually manifests as iron deficiency anemia (IDA). Early recognition and treatment of ID/IDA in GI oncology patients is an important aspect of care. Traditional serum ferritin monitoring and oral iron supplementation hold limited diagnostic and therapeutic value in this population as it may be falsely elevated and confounded by poor absorption and blood loss, respectively. Therefore, we conducted a survey of Canadian physicians to assess disparities in IDA surveillance and management practices in GI cancer patients. Methods: From February 2020 to September 2021, a 20-question electronic survey was sent to Canadian medical oncologists (MO), surgical oncologists (SO), and gastroenterologists (GE). The survey collected information on four domains: demographics, screening practices, treatment practices, and knowledge of the latest guidelines of ID/IDA. Analysis was conducted using descriptive statistics. Results: A total of 108 (55 GE, 19 SO, and 34 MO) of the 872 (12.4%) invited physicians completed the survey. A greater proportion of GE (70.9% compared to 36.8% of SO, and 26.5% of MO) measured baseline iron parameters. Of these, a slight trend of iron parameters were being measured mainly at initial consult (61.5% of GE, 85.7% of SO, and 44.4% of MO), with little continuing surveillance throughout treatment course. Most physicians who measured iron parameters relied on ferritin mainly (82.1% of GE, 100% of SO), while MO were evenly distributed in their evaluation of ferritin (88.9%), serum iron (100%), total iron binding capacity (100%) and iron saturation (88.9%). The majority supplemented iron if ID/IDA was identified prior to systemic/surgical oncologic treatment (94.2% of GE, 85.7% SO, and 66.7% of MO). Of these, parenteral iron was the preferred modality for SO (85.7%), while oral iron was preferred among GE (82.8%) and MO (55.6%). The majority of physicians (81.3%) were not aware of the ASH/ASCO guidelines regarding the use of erythropoiesis stimulating agents in conjunction with parenteral iron supplementation for treatment anemia in this setting (92% of GE, 66.7% of SO, and 80.9% of MO). Conclusions: Results from this Canadian survey suggests a disparity in practice pattern for IDA management between different specialties caring for GI oncology patients. Moreover, there appears to be a gap in knowledge and thus a gap in care surrounding evidence-based IDA management principles which may be contributing to poor clinical outcomes. Focused knowledge translation and exchange efforts are required to improve treatment of ID/IDA in patients with GI cancer nationally.
Meta-analysis and systematic review of the role of preemptive oral antibiotics and topical vitamin K for acneiform rash induced by EGFR-targeted therapies.
Authors: Costa Lima Andre Bacellar , Sasse Andre Deeke 
Published: June 2022

e13646 Background: Acneiform rash (AR) is the most frequent adverse event associated with epidermal growth factor receptor (EGFR) inhibitors, which are widely used to fight solid tumors. Multiple trials studied prophylactic measures to help prevent the incidence and severity of this skin toxicity. The aim of this systematic review and meta-analysis (MA) was to analyze the clinical efficacy of the two most studied prevention strategies to mitigate the severity of skin rash induced by EGFR inhibitors. We sought to understand the current role of oral antibiotics and topical vitamin K in this scenario. Methods: A wide search through electronic databases and congress abstracts was performed. Studies with control groups reporting the pre-emptive role of both oral antibiotics and topical vitamin K were selected for two separate MA. Overall incidence and severity of AR were the analyzed dichotomous outcomes. Results: Fourteen studies (n=1085) were included in the antibiotics MA. Antibiotics prevented both moderate to severe (OR 0.38; CI 95% 0.24-0.60) and all-grade AR (OR 0.55; CI 95% 0.39-0.78). Four studies (n=507) were selected for the vitamin K MA. No benefit in the prevention of grade ≥ 2 AR was observed for this topic agent in the prophylactic setting (OR 1.21; CI 95% 0.79-1.85). Conclusions: There is still need to seek more efficacious ways to manage skin toxicities associated with EGFR inhibitors since this can impair quality of life and cancer treatment adherence. The use of oral antibiotics should be more encouraged as a prophylactic measure in the current guidelines.
A rare subtype of the glial tumor with H3F3B p.K28I in Chinese adult diffuse midline gliomas.
Authors: Ding Feng , Luo Ningning , Han Tiantian , Guo Didi , Lu Guanghua , Bu Fanfeng 
Published: June 2022

e14012 Background: Diffuse midline gliomas (DMGs) with H3 K27 altered are extremely aggressive WHO grade IV tumors, with no significant therapeutic progress made in the past. DMGs with H3 K27 altered have been classified as a rare subtype of glial tumor according to 2021 WHO Classification of CNS Tumors. K27M mutation always occurs in the H3F3A gene or HISTIH3B/C gene, and the majority of DMGs harbor H3 K27M-mutation. Studies have been reported that systematic in vitro modification of the lysine 27 predicts K27I as the only substitution other than K27M to result in a repressive effect on H3K27me3. Herein, we reported two adult patients with DMGs harboring somatic H3-K27I mutation. It is important to identify H3 K27-mutation accurately for accurate diagnosis, prognostication, and also for treatment selection. Methods: Next-generation sequencing (NGS) 539-gene panel (Simceredx) profiling was performed using postoperative tissue. The molecular characteristics, K3 K27 mutation types, and other co-mutations were also evaluated. Results: Patient one was a 36-year-old female. Magnetic resonance images (MRI) of the brain were performed and showed the pons tumor in the brainstem. Postoperative pathology showed astrocytoma (WHO Grade II) with diffuse slightly dense cells. NGS results showed that the patient was carried H3F3B exon2 p.K27I (allele frequency, AF 57.64%), TP53 exon7 p.M237I (AF 80.27%). Patient two was a 44-year-old male and was diagnosed with spinal cord glioma, WHO grade III. NGS panel profiling was performed and H3F3B exon2 p.K27I (AF 30.46%), ATRX exon9 p.S1173* (AF 75.23%), KRAS exon2 p.G12A(AF 38.11%) and NF1 intron42 c.6580-1G > A(AF 36.44%) were identified. Conclusions: In our study, we identified the H3F3B K27I mutation in two adult DMG patients by NGS, which expanded the detection gene spectrum of DMG patients. The type of histone H3 mutated could also predict the outcome and accurate diagnosis and glioma grading of DMG patients, which was more efficient than clinical and radiological characteristics of the tumors. Accurate genetic testing should be given more attention to those patients.
FGL2 expression and relation with survival and prognosis in patients treated with concurrent temozolamide and radiotherapy in high-grade glioma.
Authors: Elnaggar Maha , Mohamed Mohamed Alaa , Makboul Rania , El Hakeem Ahmed A.S. , Abd El-Ghani Wael M.A. , Essam Sohaila Mohammed , Eid Samir-Shehata M. 
Published: June 2022

e14019 Background: FGL2 is a member of the fibrinogen-related protein, Literature suggests that FGL2 contributes to the progression of glioblastoma multiforme (GBM) through inducing multiple immunosuppression mechanisms. The present study aimed at evaluation of the expression and the prognostic value of FGL2 in high grade glioma. Methods: In our study, we analysed sixty specimens retrieved at diagnosis of high grade glioma patients. They received concurrent Temozolamide and radiotherapy, as a standard of care, during the period from October 2019 to December 2020 and and were followed up for 12 months . Evaluation of FGL2 expression done by using FGL2 Immunohistochemistry .ClinicalTrials.gov Identifier: NCT04113278. Results: Mean age of studied patients was (48.88± 12.45) . Majority (75%) of patients were males. Mean FGL2 expression was 61 ± 31.80 (%) with range between 3% and 95%. It was found that 7 (11.7%) patients had negative FGL2. Over the period of follow up, incidence of disease progression was significantly higher among the patients with higher percentage of FGL2 in comparison to those with lower FGL2 percentages (76.54 ± 18.52 vs. 56.17 ± 33.41(%); P= 0.04). number of deaths was also significantly higher among the high FGL2 percentage group (64.86 ± 31.58 vs. 54.16 ± 31.71(%); P= 0.03). Intensity of FGL2 was mild 16 (26.7%), moderate 20 (33.3%) and strong 17 (28.3%) . Intensity of FGL2 was more among patients with disease progression. All patients with progression had either moderate intensity (46.2%) or strong intensity (53.8%). Seven (14.9%) patients without disease progression had negative FGL2 expression with ( P= 0.01). Disease free progression (DFP) was significantly negatively correlated with increasing in the intensity of FGL2. Patients with strong intensity had the lowest DFP (14 month) while patients with negative FGL2 and mild intensity had the highest DFP (25 month) with ( P <0.001). Overall survival was significantly worse with increasing in the intensity of FGL2 where patients with strong intensity had the lowest overall survival (19 month), while patients with negative FGL2 and mild intensity had the highest overall survival (27and 26 month, respectively) with ( P <0.001). For prediction of progression among patients with high grade glioma, FGL2 at cut off point > 60% has 92.3% sensitivity and 28% specificity with ( P= 0.04). For prediction of mortality among patients with high grade glioma, FGL2 at cut off point > 70% has 67% sensitivity and 61% specificity with ( P= 0.03). Conclusions: FGL2 expression in high grade glioma patients can be used as a prognostic factor but additional studies are required to clarify the prognostic value.
Comprehensive analysis of non-transplant central nervous system lymphoproliferative disease associated with immunosuppressant use.
Authors: Tadipatri Ramya , Ekhator Chukwuyem , Narayan Ram , Azadi Amir , Yuen Kevin C.J. , Grewal Jai , Fonkem Ekokobe 
Published: June 2022

e14043 Background: Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens, with additional survival benefit gained by CD-20 targeting with rituximab. With increasing prevalence of autoimmune disease and a corresponding rapid rate of development and approval of new immunosuppressant medications, a new type of lymphoproliferative disorder (LPD) has been described, known as iatrogenic immunodeficiency associated LPD. These disorders are typically EBV positive and have distinct histologic and genetic features. Furthermore, many of them arise in the setting of prior methotrexate use, raising the question of whether standard HD-MTX based regimens would still be effective. Our objective was to further characterize this disorder, with a focus on cases with central nervous system involvement, and to determine the optimal management strategy. Methods: We describe a case of a 76-year-old female with iatrogenic immunodeficiency associated PCNSL following 10 years of mercaptopurine, which was successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency associated LPD involving the central nervous system (CNS). We used a linear probability statistical model to determine correlations with outcome. Results: While the majority of immunosuppressants were associated with EBV positive tumors, natalizumab was associated with EBV negative tumors (95% CI -0.951, -0.076), and EBV positive tumors were associated with improved outcomes (95% CI 0.074, 0.687). Surgical resection (95% CI 0.028, 0.574) was associated with improved outcomes, although limited by potential confounding effect. Although they did not reach statistical significance, antiviral treatment (95% CI -0.039, 0.459) and rituximab (95% CI -0.073, 0.524) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. Conclusions: Based on this data, we propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency associated LPD of the CNS. However, further study through randomized clinical trials is warranted.
Early safety and efficacy from a phase I open-label clinical study of LVGN7409 (CD40 agonist antibody) in patients with advanced or metastatic malignancies.
Authors: Fu Siqing , Vandross Andrae Lavon , Hsu Yi Hsin , Shi Naiyi , Jiang Lynn , Su Fusheng , Wang Jieyi , Chan C. Hubert 
Published: June 2022

e14501 Background: LVGN7409 is a recombinant monoclonal antibody against CD40. The modified Fc fragment binds FcγRIIB selectively. LVGN7409 activates CD40 in Fc-FcγRIIB cross-link dependent manner and thus optimally in CD40 and FcγRIIB enriched tumor microenvironment. LVGN7409 demonstrated more robust antitumor efficacy and superior safety profile than published CD40 agonist antibodies in preclinical models. An open-label, first in human phase 1 study of LVGN7409 as a single agent, combined with LVGN3616 (anti-PD-1 antibody), and combined with LVGN3616 and LVGN6051 (CD137 agonist antibody) is ongoing. Methods: LVGN7409 was given intravenously every 3 weeks. For single agent dose-finding, LVGN7409 accelerated doses from 0.01 to 0.1mg/kg, and then conventional “3 + 3” design from 0.3 mg/kg. The objectives evaluate LVGN7409 safety, RP2D in a single agent and combination therapy, PK, immunogenicity, preliminary antitumor activity, and exploratory PD biomarkers. Results: As date on January 24, 2022, 12 patients (5 males, 7 females; median age 56, range 29-76; all ECOG 1 at screening; median 6 lines of prior therapies, range 2-14) have been treated with LVGN7409 monotherapy into 6 cohorts (0.01-0.03mg/kg n=1, 0.1-0.3mg/kg n=3, 1mg/kg n=6, 2mg/kg n=2). They received a median of 3 (range 1-10) treatment cycles. No DLT event was observed up to 2mg/kg of LVGN7409. Treatment-related adverse events (TRAEs) of any grade occurred in 10 out of 12 patients (n=10) including infusion related reaction (n=7), amylase increased (n=5), lipase increased (n=5), ALT increased (n=5), AST increased (n=5), bilirubin increased (n=1), WBC or neutrophil decreased (n=1), nausea (n=1), and cytokine release syndrome (n=1). Two patients experienced grade 3 TRSAEs: amylase/lipase increased (n=1) and ALT/AST increased (n=1). Most TRAEs were transient, asymptomatic, self-limited, and occurred in the initial cycle without recurrence upon rechallenge. Four of nine evaluable patients (44%) hadstabledisease by RECIST1.1 and iRECIST, with one active patient being treated for more than 8 months. CD40 receptor occupancy was achieved at the dose of 0.3 mg/kg and above; preliminary pharmacodynamic marker changes were observed. Conclusions: Preliminary evidence showed LVGN7409 monotherapy was well tolerated up to 2mg/kg. Approximately 44% of stable diseases were observed in these heavily treated patients. The favorable safety profile and preliminary antitumor activity warrant further evaluation of LVGN7409 as a single agent and in combination with other cancer therapeutics in patients with advanced malignancies. Clinical trial information: NCT04635995.
SNS-101, a highly selective monoclonal antibody against the active form of VISTA, demonstrates significantly reduced cytokine release.
Authors: van der Horst Edward , Jiang Zhi-Gang , Malhotra Kanam , Mukherjee Arnab , Biesova Zuzana , Cifuentes Anokhi , Thisted Thomas , Pierce Robert Hamilton , Martin Gaëlle , Thiam Kader 
Published: June 2022

e14504 Background: Active cancer immunotherapeutics frequently give rise to immune-mediated adverse events (AEs), including cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). On-target, off-tumor activation of myeloid lineage cells (e.g. monocytes) has been implicated as a factor in the generation of these immune-mediated AEs. VISTA (V-domain Ig suppressor of T-cell activation) is an immune checkpoint, which is highly expressed on myeloid cells, and binds PSGL-1 on T-cells, but only when ‘activated’ by protonation at low pH (̃pH 6). Inhibition of the VISTA:PSGL-1 interaction in the acidic tumor microenvironment has been shown to be efficacious in multiple syngeneic murine tumor models. However, antibodies binding to VISTA at physiological pH 7.4 have significant potential to induce dose-limiting toxicities such as CRS and/or ICANS and be prematurely eliminated from circulation through targeted-mediated drug disposition (TMDD), reducing the likelihood of reaching efficacious drug occupancy levels. Among several non-pH-selective antibodies in clinical development, JNJ-61610588 (now CI-8993) induced dose-limiting on-target CRS at subtherapeutic dose levels and exhibited TMDD. To mitigate potential CRS and prevent TMDD, we developed SNS-101, a highly selective monoclonal IgG1 antibody for “active” VISTA, which inhibits the critical interaction with PSGL-1. Methods: Using flow cytometry at physiological pH, we compared SNS-101 with clinical stage non-pH-selective anti-VISTA antibodies and examined binding to VISTA-positive cell populations in human PBMCs as well as in human CD34+ cord blood cells reconstituted BRGSF-HIS mice (humanized BRGSF-HIS mice), which develop both human lymphoid and myeloid compartments. Furthermore, we performed in vitro and in vivo CRS studies in a HUVEC/PBMC co-culture system and humanized BRGSF-HIS mice, respectively. Results: Under physiological pH, non-pH-selective antibodies bound to monocytes, neutrophils and NK cells whereas SNS-101 did not exhibit any significant interactions. CRS assays indicate that the magnitude of induced cytokine levels was significantly higher with non-pH-selective antibodies compared to SNS-101. Conclusions: We assessed the binding profile of SNS-101 vs. non-pH-selective VISTA antibodies. Our results demonstrate that SNS-101 does not bind to VISTA-positive cells in circulating blood. In addition, in vitro and in vivo CRS studies suggest that SNS-101 has a lower risk of inducing CRS compared to non-pH selective anti-VISTA antibodies, alleviating liabilities previously associated with anti-VISTA antibodies. IND-enabling studies, including pharmacokinetic and toxicology studies, are ongoing.
Characteristics of CRC01, an investigational CD19 CAR-T product with PD-1 and TIGIT genes silenced by shRNAs.
Authors: Park YoungSam , Jeon Dong-Hyuk , Yi Hyunhwan , Lee Sang-Hoon , Kim Hyung Cheol 
Published: June 2022

e14514 Background: Currently, CAR-T therapy has been successful in the treatment of certain types of hematological malignancy. However, not all patients benefit from this novel therapy due to various resistance mechanisms, such as suppression of immune cell function by inhibitory immune checkpoint signaling. To overcome this, we have developed a novel two-in-one lentiviral vector system that can efficiently induce shRNA-based silencing of PD-1 and TIGIT genes in CAR-T cells while maintaining robust CAR expression. This PD-1 and TIGIT-silenced CD19 CAR-T, CRC01, showed an enhanced anti-tumor activity in vitro and in vivo, compared to conventional CD19 CAR-T. For the development of CRC01 as an investigational new drug, IND-enabling non-clinical studies have been conducted and CRC01 is currently being evaluated in a clinical trial for r/r LBCL patients (NCT04836507). Methods: T cells were enriched from leukapheresis products of r/r LBCL patients and transduced with the two-in-one lentiviral vector. Transduced T cells were expanded within a semi-closed culture system and formulated for cryopreservation. For phase I clinical trial of CRC01, ten batches of CRC01 were manufactured and characterized in quality. Results: In the manufacturing of ten batches of CRC01, manufacturing time was in the range of 8-14 days and total cells expanded 32-53 folds. In the final product of CRC01, T cell percentage (Live CD3+) and viability were not less than 98% and 85%, respectively. The range of transduction efficiency was 11.3%-28.6% and the range of vector copy number was 1.0-3.5 copies/CAR-T. Generally, CRC01(CAR-positive T cells) showed higher CD4/CD8 ratio than leukapheresis product and CAR-negative T cells, and central memory and effector memory T cell subsets were the main populations of CRC01. All batches of CRC01 released IFN-γ in response to CD19-expressing target cells, but the level of IFN-γ production was quite different from batch to batch. When PD-1 and TIGIT expression levels of CRC01 were analyzed after CD3/CD28 stimulation, CAR-positive T cells were found to express PD-1 and TIGIT much lower than CAR-negative T cells, demonstrating an efficient silencing of PD-1 and TIGIT genes in CRC01. Conclusions: Ten batches of CRC01 were manufactured in GMP facility for CRC01 phase I clinical trial. All batches met acceptance criteria for release, showing that CRC01 manufacturing process is a robust one and that silencing of PD-1 and TIGIT genes via shRNAs, a unique feature of CRC01, was successfully implemented in the investigational products.