CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA

alexandrossfakianakis shared this article with you from Inoreader CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA via # Neuro-Oncology Current Issue Abstract Glioblastoma is the most aggressive primary brain tumor and adults and poorly immunogenic. Treatment options for recurrent glioblastoma after standard of care chemoradiation are limited Several immunotherapeutic strategies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival and except from potentially regorafenib, no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigate a new treatment combination based on the alkylating chemotherapy lomustine and the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and patients with recurrent glioblastoma. The combination treatment with lomustine and L19TNF demonstrated strong synergistic anti-tumor activity in several immunocompetent orthotopic glioma models curing the majority of tumor-bear ing mice, whereas other mono- or combination therapies for example with anti-PD1 had only limited anti-glioma activity. Investigations of the mechanism of action revealed that lomustine plus L19TNF led to intratumoral necrosis, DNA damage and triggered a strong local anti-tumor immune response with increased MHC-I expression, presentation of neoepitopes and increased abundance of tumor-infiltrating lymphoid cells. In the first patients treated within a phase I/II clinical trial (NCT04573192), the treatment was well tolerated, and durable objective tumor responses and disease stabilizations could be observed also in patients with an unmethylated MGMT promoter. View on Web

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STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA

alexandrossfakianakis shared this article with you from Inoreader STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA via # Neuro-Oncology Current Issue Abstract Glioblastoma (GBM), a high grade brain tumor, possesses poor overall survival with less than 5% surviving past five years. Previously, the TCGA classifications for GBM have included the mesenchymal, proneural, classical and neural subtypes with their own respective expression profiles and survival. Recent omics analysis has revealed other key aspects of GBM pathology, including intratumoral heterogeneity spanning all subtypes and enhanced stemness and treatment resistance and other hallmarks of proneural mesenchymal transition (PMT) following treatment with first-line standard of care treatment with radiation therapy and temozolomide (TMZ). Invading glioma stem cells (GSC) with high Nestin and hypoxia-inducible factor 1 alpha (HIF-1α) expression have been theorized to contribute to recurrence. HIF-1α acts as a master regulator driving increased stemness, invasiveness and angiogenesis. Interestingly, HIF-1α and nuclear respiratory factor-2 both upregulate Lon peptidase 1 (LonP1) in response to increased hypoxia or reactive oxygen species (ROS) production. LonP1 has been shown to drive increased metastasis, tumor growth and epithelial-mesenchymal transition (EMT), an analog of PMT, in colon cancer, melanoma and other cancer types. In a recently elucidated GBM organoid model, we present new findings demonstrating the importance of LonP1 in driving enhanced, transient PMT near the 'invading edge'. This includes the enhanced expression of several key drivers of PMT and phenotypic hallmarks, such as increased invasiveness, proliferation and poorer survival. View on Web

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LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses

alexandrossfakianakis shared this article with you from Inoreader LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses via # Neuro-Oncology Current Issue Abstract OBJECTIVE Cellular heterogeneity determines tumor phenotype and response to therapy. This is particularly pronounced in glioblastoma (GBM), which is characterized by multiple malignant cell states with distinct proliferation potentials, and different cell types of the microenvironment. Ideally, cellular heterogeneity is characterized using single cell genomic profiling techniques. However, these techniques remain challenging to apply in a diagnostic setting and to large retrospective patient cohorts (TCGA, GLASS, DKFZ and clinical trials). Instead, clinicians routinely support their diagnosis with bulk DNA methylation profiling, which generates robust results from low quality material but does not inform on cellular heterogeneity. We have developed a powerful new computational method to deconvolute bulk DNA methylation data and infer cellular heterogeneity within individual tumors, to support prognostic accuracy and personalized treatme nt decisions. METHODS Using both bulk and single-cell multi-omic datasets, we created a DNA methylation-based reference of cell types (malignant, glial, neuronal, and immune) within GBM tumors, and the state of malignant cells therein (stem-like vs. differentiated-like). Using this reference, our computational approach accurately deconvolutes bulk DNA methylation profiles of individual query samples. RESULTS High deconvolution accuracy of GBM heterogeneity was achieved from frozen and FFPE tissue samples, including those of low quality or purity (Jensen Shannon divergence for composition similarity < 0.05). Our approach eliminates bias derived from the microenvironment, and results in patient stratification that harmonizes the DNA methylation- and RNA-based classifications of GBM. It also reveals the inter- and intra-tumoral links between the genetic, DNA methylation, and transcriptomic components of GBM pathology, and suggests their specific impacts on treatmen t efficacy. To facilitate clinical translation, we created a public website that allows clinicians to infer the relative abundance of different cell states within a tumor at the click of a button. View on Web

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Pediatric cancer‐associated thrombosis

alexandrossfakianakis shared this article with you from Inoreader Pediatric cancer‐associated thrombosis: Analysis from a tertiary care cancer center in India via Pediatric Blood & Cancer Abstract Background and aims Thrombotic events (TEs) have been extensively studied in adult cancer patients, but data in children are limited. We prospectively analyzed pediatric cancer-associated thrombosis (PCAT) in children with malignancies. Methods Children below 15 years of age with confirmed malignancies, treated at a large tertiary cancer center in India from July 2015 to March 2020 developing any TE were eligible. A standardized approach for detection and management was followed. Data were collected after informed consent. Results Of 6132 eligible children, 150 (2.44%) had 152 TEs, with median age 8.5 years and male:female of 1.83:1. Most TEs occurred on chemotherapy: 111 (74.0%). The most common site was central nervous system (CNS) 59 (39.3%), followed by upper-limb venous system 37 (24.7%). Hemato-lymphoid (HL) malignancies were more prone to PCAT than solid tumors (ST) (incidence 3.23% vs. 1.58%; odds ratio [OR] = 2.06, 95% confidence interval [CI] [1.36–2.88]; p < .001). Malignancies associated with PCAT were acute lymphoblastic leukemia (ALL) 2.94%, acute myeloid leukemia (AML) 6.66%, and non-Hodgkin lymphomas 5.35%. Response imaging done in 106 (70.7%) children showed complete to partial resolution in almost 90% children. Death was attributable to TE in seven (4.66%) children. Age above 10 years (OR 2.33, 95% CI [1.59–3.41]; p < .001), AML (OR 4.62, 95% CI [1.98–10.74]; p = .0062), and non-Hodgkin lymphoma (OR 4.01, 95 % CI [1.15–14.04]; p = .029) were significantly associated with TEs. In ALL, age more than 10 years (OR 1.86, 95% CI [1.06–3.24]; p < .03), T-ALL (OR 3.32, 95% CI [1.69–6.54]; p = .001), and intermediate-risk group (OR 4.97, 95% CI [1.12–22.02]; p = .035) were significantly associated with thrombosis. The 2-year event-free survival (EFS) for HL malignancies with PCAT was 55.3% versus 72.1% in those without PCAT (p = .05), overall survival (OS) being 84.6% versus 80.0% (p = .32). Conclusion Incidence of PCAT was 2.4%, and occurred predominantly in older children with hematolymphoid malignancies early in treatment. Most resolved completely with low molecular weight heparin (LMWH) and mortality was low. In hematolymphoid malignancies, PCAT reduce EFS, highlighting the need for prevention. View on Web

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18F‐fludeoxyglucose positron emission computed tomography (18F‐FDG‐PET/CT) versus 68Ga‐DOTATATE‐PET/CT in patients with head and neck cancer: Comparisons and implications for treatment

alexandrossfakianakis shared this article with you from Inoreader 18F‐fludeoxyglucose positron emission computed tomography (18F‐FDG‐PET/CT) versus 68Ga‐DOTATATE‐PET/CT in patients with head and neck cancer: Comparisons and implications for treatment via Head & Neck Abstract Background Tumor-specific molecular imaging in head and neck squamous cell carcinoma (HNSCC) is not well established. Somatostatin receptors (SSTRs) are found in solid tumors, including HNSCC. 68Ga-DOTATATE, a commercially available radionuclide that binds SSTRs, may have utility in imaging HNSCC. Methods Patients with HNSCC received pretreatment imaging with 18F-FDG-PET/CT and 68Ga-DOTATATE. Imaging was compared for concordance. When available, surgical resection specimens were compared to pretreatment imaging findings. Historic HNSCC tumor specimens were assessed for both SSTR and p16/human papilloma virus (HPV) expression. Results Twenty patients were imaged. Fifteen had oropharyngeal cancer. Primary tumor site was concordant between imaging modalities for all patients. One of 45 lymph nodes was discordant. Retrospective specimen review showed a significant correlation with SSTR expression and HPV/p16 expression. No adverse events occurred. Conclusions 68Ga-DOTATATE imaging is safe and effective in HNSCC. SSTR expression may be increased in HPV-mediated tumors. Targeted therapies to SSTR should be explored. View on Web

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Emergence of recombinant norovirus GII.12[P16] and predominance of GII.3[P12] strains in pediatric patients with acute gastroenteritis in Thailand, 2019‐2020

alexandrossfakianakis shared this article with you from Inoreader Emergence of recombinant norovirus GII.12[P16] and predominance of GII.3[P12] strains in pediatric patients with acute gastroenteritis in Thailand, 2019‐2020 via Journal of Medical Virology ABSTRACT Norovirus (NoV) and sapovirus (SaV) are important pathogens that cause acute gastroenteritis (AGE) in all age groups, commonly in children worldwide. Recently, a number of studies have reported a wide variety of NoV recombinant strains. This study aimed to investigate the distribution of NoV and SaV recombinant strains circulating in Chiang Mai, Thailand during 2019-2020. One hundred and twenty-four NoV and seven SaV strains detected in children admitted to the hospital with AGE were included in this study. The partial RdRp/VP1 regions of these NoV and SaV strains were analyzed by phylogenetic analysis, Simplot and RDP softwares. Overall, eight recombination patterns of NoV were detected. NoV GII.4[P16] was the most common strain detected (39.1%), followed by GII.3[P12] (25.0%), GII.4[P31] (17.2%), and other recombinant strains were detected at lower rate. NoV GII.12[P16] strains were detected for the first time in Thailand. For SaV, none of the recombinant strains was detected. All SaV strains, GI.1/GI.1, GI.2/GI.2, and GII.5/GII.5, exhibited VP1 genotype corresponded to RdRp genotype. In conclusion, this study demonstrates the distribution and diversity of NoV and SaV recombinant strains circulating in pediatric patients with AGE in Chiang Mai, Thailand during 2019-2020 with the emergence of NoV GII.3[P12] and GII.12[P16]. This article is protected by copyright. All rights reserved. View on Web

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Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation

alexandrossfakianakis shared this article with you from Inoreader Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation via Pediatric Blood & Cancer Abstract Background Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. Procedure We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose—busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor t herapies. Results With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II–IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). Conclusions Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD. View on Web

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