bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep learning-based brain tumor segmentation on limited sequences of magnetic resonance imaging.
Authors: Huang Jacky , Molleti Powell , Iv Michael , Lee Richard , Itakura Haruka 
Published: June 2022

2054 Background: Deep learning algorithms trained to segment brain tumors from magnetic resonance imaging (MRI) perform well in ideal conditions supplied by curated datasets. An example is the MICCAI BraTS 2018 dataset, which provides a set of four MRI sequences (T1, T1 post-gadolinium contrast-enhanced, T2, FLAIR) on 285 samples, along with ground truth segmentations annotated by experts. In real-world settings, however, it is not uncommon for patients to undergo MRI with a limited number of image sequence acquisitions. We examined the effect of restricting the imaging sequence set when training a deep learning model for brain tumor segmentation. Our goal was to identify a limited subset that still achieved acceptably high performance. Methods: In our experiments, we used the convolutional neural network-based U-Net architecture. Instead of the standard BraTS task, we focused on sub-segmenting specific areas of brain tumors: the active, enhancing tumor (AT) and the tumor core (TC; AT plus the cystic/necrotic core). We trained the architecture on 285 samples of the BraTS 2018 dataset using one or both of two sequences: T1 contrast-enhanced (T1CE) and FLAIR. Using each training model, we predicted segmentation masks given a volumetric MR image of a brain tumor on 66 samples in the held-out validation dataset. We submitted the predicted segmentations to the Center for Biomedical Image Computing and Analytics (CBICA) imaging portal for evaluation, which reports prediction accuracy by returning dice scores on each prediction. Results: As shown in the Table, the U-Net model using T1CE alone yielded high performances, with median dice scores of 0.84461 and 0.88267, when segmenting AT and TC, respectively. On the other hand, using FLAIR alone generated lower performances on the same tasks of segmenting the AT (0.25996) and the TC regions (0.51153). Combining T1CE and FLAIR provided no additional performance improvement compared with T1CE used as a standalone sequence. Conclusions: We achieved high performances in two brain tumor sub-segmentation tasks using a limited number of MRI sequences in training a deep-learning algorithm. T1CE alone produced high performances on both TC and AT segmentations. Given the ubiquity of the T1CE sequence, the ability to achieve high performance tumor segmentations in the face of limited image sequence availability is critical when applying our algorithm in real-world clinical or research settings. [Table: see text]
Prostate-specific membrane antigen expression in meningioma.
Authors: Elinzano Heinrich , Tubre Teddi , Hacking Sean , Alexander Abigail , Brickman Arlen , Delalle Ivana , Donahue John 
Published: June 2022

2072 Background: Meningioma is the most common CNS tumor, yet there is no effective therapy for relapsed/refractory meningioma after surgery and radiation therapy. Although most meningiomas follow a relatively benign course, some have a more aggressive course with rapid tumor growth, brain invasion, higher recurrence rates or extracranial metastasis. Prostate-specific membrane antigen (PSMA) is a transmembrane peptidase upregulated on endothelial cells of malignant solid tumors including glioblastoma and metastatic brain tumors, but not in normal vasculature. PSMA has been investigated as a therapeutic target and as a molecular imaging marker to monitor response to treatment and evaluate disease activity in PSMA-avid tumors. PSMA expression however has not been studied in meningioma. Methods: Archival tumor specimens (96 tumor samples: 58 WHO grade 1, 35 WHO grade 2, 3 WHO grade 3) from 69 patients were stained for H&E, PSMA and CD31 and slides were scanned (Leica Aperio AT2 whole slide image scanner). 37 of these samples were recurrent tumors and 13 had prior radiation therapy (intensity-modulated, Gamma knife, craniospinal). 21 of the 69 patients had paired samples of initial and recurrent tumors. QuPath was utilized as open access solution to machine learning generating raw data for PSMA, CD31, PSMA/CD31 ratio and PSMA/vasculature ratio. Paired t-test, unpaired t-test and ROC curves were used for statistical analysis. Results: PSMA expression was seen in all of the study samples. PSMA expression (p = 0.0147) was lower in grade 1 compared to grade 2 and 3 tumors, but not different among histologic subtypes. PSMA/vasculature ratio (p = 0.0015) was lower in grade 1 compared to grade 2 and 3 tumors. PSMA expression (p = 0.002) and PSMA/vasculature ratio (p = 0.0015) were higher in recurrent compared to non-recurrent tumors. PSMA expression (p = 0.0442) was higher in recurrent compared to initial tumors among paired samples. When comparing initial tumors of paired samples to non-recurrent tumors, ROC curves demonstrated CD31 expression (AUC:0.7278; p = 0.0008), PSMA/CD31 ratio (AUC:0.7843; p = < 0.0001) and PSMA/vasculature ratio (AUC:0.6256; p = 0.0328) to be predictors of tumor recurrence. Tumors with prior radiation therapy had higher PSMA/vascular ratio (p = 0.0439) compared to those without. Conclusions: PSMA is expressed in tumor vasculature of meningioma of any grade, increases at recurrence and persists with prior radiation therapy. Since it is present in meningioma of different grades and throughout the course of the disease, it could potentially be utilized as consistent diagnostic biomarker, relevant factor for risk of recurrence stratification and novel therapeutic target for these tumors.
Single-cell profiling of human heart and blood in immune checkpoint inhibitor-associated myocarditis.
Authors: Blum Steven Michael , Zlotoff Daniel A. , Smith Neal , Ramesh Swetha , Kernin Isabela , Sen Pritha , Zubiri Leyre , Tirard Alice , Nasrallah Mazen , Tantivit Jessica , Barth Jaimie Lynn , Juric Dejan , Sullivan Ryan J. , Boland Genevieve Marie , Mino-Kenudson Mari , Stone James , Thomas Molly , Reynolds Kerry Lynn , Neilan Tomas G. , Villani Alexandra-Chloé 
Published: June 2022

2507 Background: Myocarditis due to immune checkpoint inhibitors (ICIs) is uncommon; however, myocarditis due to ICIs leads to severe morbidity and even death in 20-40% of cases. The molecular underpinnings of ICI-associated myocarditis are poorly understood, and there is an unmet clinical need to identify therapeutic targets and biomarkers that can aid in disease management. Methods: Heart tissue was obtained through endomyocardial biopsy or autopsy of patients receiving ICIs and was profiled with paired single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (TCR) using the 10x Genomics Chromium system. A control dataset was constructed using scRNAseq data of heart tissue from patients receiving ICIs but without myocarditis and a published dataset from healthy patients not receiving ICIs. Peripheral blood mononuclear cells (PBMCs) were collected at the time of myocarditis diagnosis in a larger cohort of patients and analyzed with ICI-treated controls. The CITE-Seq protocol was used to measure paired scRNA-seq, TCR, and surface proteomics in PBMCs, using serial timepoints where available. Results: Heart tissue from 13 patients with myocarditis, including three fatal cases, and seven controls yielded 77,712 single cells. Blood profiling from 27 patients with ICI myocarditis and ICI-treated controls across 54 samples yielded over 230,000 cells. ICI myocarditis tissue demonstrated an increased T cell infiltrate (OR 8.94, FDR = 0.0021). Expression of multiple inflammatory pathways, most notably interferon responses, was up-regulated across multiple immune and non-immune cell types in the setting of myocarditis, providing important pathophysiological insights. T cell clones were also found to be shared between blood and heart, enabling the identification of putative pathogenic T cell subsets. Conclusions: Increased intramyocardial T cells and the activation of interferon response gene networks were seen in the setting of ICI myocarditis. These preliminary findings highlight potential pathological pathways in ICI myocarditis that could serve as biomarkers or therapeutic targets.
External validation of the VIGex gene-expression signature (GES) as a novel predictive biomarker for immune checkpoint treatment (ICT).
Authors: Hernando-Calvo Alberto , Yang S Y Cindy , Vila-Casadesús Maria , Berman Hal K. , Spreafico Anna , Abdul Razak Albiruni Ryan , Lheureux Stephanie , Hansen Aaron Richard , Lo Giacco Deborah , Matito Judit , Pugh Trevor John , Bratman Scott Victor , Berché Roger , Saavedra Santa Gadea Omar , Garralda Elena , Elston Sawako , Siu Lillian L. , Ohashi Pamela S. , Vivancos Ana , Bedard Philippe L. 
Published: June 2022

2510 Background: VIGex is a 12- gene GES classifier initially developed on the Nanostring platform and validated for RNA-seq. VIGex classifies samples into Hot, intermediate-Cold (I-Cold) and Cold subgroups. The Hot subgroup as defined by VIGex has been associated with better (PFS) in patients (pts) treated on phase 1 ICT trials at Vall D’Hebron Hospital (VH) (ESMO2020). We investigated the performance of VIGex in pts treated with Pembrolizumab (P) in the INSPIRE clinical trial (NCT02644369) at Princess Margaret Cancer Centre (PM) and compared VIGex with other predictive ICT biomarkers. Methods: Pts with advanced solid tumors were treated with P 200 mg IV Q3wks. RNA-seq from baseline biopsies was performed using the Illumina NextSeq550 platform. Tumor RNA-seq data were transferred from PM to VH and classified by the VIGex algorithm blinded to clinical data. Bespoke circulating tumor DNA (ctDNA) was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera). Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per megabase and PD-L1 was assessed by immunohistochemistry (22C3). Hot subgroup (HOT) was compared to I-Cold + Cold (COLD). We defined 4 groups based on the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). Survival times were calculated with the Kaplan–Meier method and Cox proportional-hazard models were constructed. Results: Out of 76 pts, median age was 55y (range 21-81y), M:F 31:45, all ECOG 0-1, 16 High-grade serous ovarian, 12 triple negative breast, 12 head and neck, 10 melanoma and 26 other. Median no. of P cycles was 3 (range 1–35); follow up was 14m (range 1-67); Median PFS 10.9m and median overall survival (OS) 14m. Overall response rate (RECIST 1.1) was 24% in HOT and 10% in COLD (p = 0.22 two-sided Fisher's exact test). The HOT subgroup was significantly associated with higher OS and PFS when included in a multivariate model adjusted by tumor histology, TMB and PD-L1 (HR 0.43; 95%CI 0.23-0.81; p = 0.009) and (HR: 0.48; 95%CI 0.25-0.95; p = 0.036) respectively. A total of 57 pts had both VIGex and ΔctDNA data. The addition of ΔctDNA further improved the predictive performance of VIGex for OS (Table). Conclusions: VIGex maintained its predictive power for ICT outcomes when applied to an independent external dataset using RNA-seq. The predictive information provided by VIGex was independent of PD-L1 and TMB. Our data indicates that the addition of ΔctDNA to baseline VIGex may refine prediction for ICT outcomes. [Table: see text]
Identifying mechanisms of acquired immune escape from sequential, paired biopsies.
Authors: Hodi F. Stephen , Spigel David R. , De Andrea Carlos E. , Sanmamed Miguel F. , Garralda Elena , Tabernero Josep , Gomez-Roca Carlos A. , Szabados Bernadett , Powles Thomas , Pachynski Russell Kent , Fong Lawrence , Rizvi Naiyer , Yoon Shinkyo , Kim Tae Won , Oh Do-Youn , Nicholas Alan , Tea Joy S. , Abbas Alexander R. , Price Richard 
Published: June 2022

2519 Background: Resistance to immune checkpoint blockade (ICB) can manifest as disease progression either at the initiation of treatment (primary resistance) or after some initial response (acquired resistance). To better understand the mechanisms underlying acquired resistance, the imCORE Network is conducting a study (NCT03333655) to examine changes in tumor biology from pre-treatment to disease progression across cancer types. Methods: Eligible patients included those experiencing clinical benefit on ICB (defined as objective response or stable disease longer than 6 months) and had evaluable tissue samples from both pre-treatment and within 30 days of progression. Samples were subjected to whole exome sequencing (WES), RNA sequencing (RNA-Seq), and immunohistochemistry (IHC). Whole blood samples or adjacent normal tissue were used as a reference for tumor variant calling. Results: As of December 3rd, 2021, 24 enrolled patients have complete sample pairs. Of those, melanoma, bladder, and lung were most common (n = 7, 6 and 5 pairs, respectively), but our cohort also included patients with breast cancer, squamous head & neck, and renal cell carcinoma. IHC data unexpectedly showed a modest, but consistent increase in tumor infiltrating CD8+ T cells at progression. In addition, IHC evidence of a decrease in MHC-I proteins (HLA-A and B2M) suggest that in 5 out of 24 cases, key proteins needed for antigen presentation are lost. Global differential gene expression analysis showed that immune gene expression was significantly increased at progression, including numerous chemokines and significant enrichment in gene sets responsible for antigen presentation machinery. Protein-altering mutations at progression appeared in B2M in one patient, and CXCL9 in another. However, in most cases it is unclear what genetic alterations are responsible. We do not observe evidence of consistent IFNγ and Jak/stat signaling loss or antigen presentation loss. Conclusions: While ICB resistance is thought to be associated with a lack of immune response within the TME, we found that acquired resistance is usually associated with either maintenance or an increase in immune infiltration. Multiple alterations that are unique to individual patients also continue to emerge. Our data shows ICB resistance is multifactorial and associated with dynamic changes to markers amid immune activation and inhibition. Clinical trial information: NCT03333655.
The impact of COVID-19 infection on immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors.
Authors: Guo Mengni , Liu Jieying , Ahmed Zohaib , Yu James , Miao Ruoyu , Guan Jian , Esmaeil Pour Mohammad Ali , Khayyat Azadeh , Grove Angela , Manoucheri Manoucher , Socinski Mark A. , Mekhail Tarek 
Published: June 2022

2525 Background: Immune checkpoint inhibitors (ICIs) can cause a variety of inflammatory autoimmune tissue damage, referred to as immune-related adverse events (irAEs). COVID-19 is associated with increased amounts of proinflammatory cytokines, which may synergistically affect the outcome of irAEs. Data are limited regarding the impact of COVID-19 on irAEs in ICI-treated cancer patients. Methods: We retrospectively analyzed adult patients with malignant solid tumors treated with ICIs at AdventHealth Orlando between August 2020 and August 2021. All COVID-19 infections were confirmed by PCR. Patients who had the most recent ICI treatment over one month before or after the positive COVID-19 test were excluded from the study. For COVID-19 positive group, only the irAEs that developed after COVID-19 infection were considered as events. Results: A total of 579 patients were included in our study, with 46 (7.9%) in COVID-19 positive group, and 533 (92.1%) in COVID-19 negative group. The baseline characteristics of patients in the two groups were similar in terms of age, ethnicity, ECOG, cancer histology, and type of ICI. With a median follow-up of 10 months (1-73 months), no differences in the time from ICI initiation to irAE onset, corticosteroid use, or additional immunosuppressant use were seen. A trend in higher incidence of all-grade diarrhea/colitis (8.7% vs. 3.0%, p=0.07) and grade 3 and 4 hepatitis (4.3% vs. 0.8%, p=0.08) was noted in the COVID-19 positive group, however the difference was not statistically significant. No significant difference in the incidence of pneumonitis (2.2% vs. 1.1%, p=0.44), nephritis (2.2% vs. 0.8%, p=0.34) or dermatitis (6.5% vs. 6.4%, p=1.00) were noted between COVID-19 positive and negative groups. We noticed a higher incidence of all-grade irAEs in the COVID-19 positive group (30.4% vs. 19.9%, p=0.18), but the difference was not statistically significant. The incidence of grade 3 and 4 irAEs was significantly higher in the COVID-19 positive group (10.9% vs. 3.2%, p=0.02). Nine COVID-19 related death occurred while no irAE-related death was noted in the entire cohort. Conclusions: Our study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possible delaying ICI administration could be considered when cancer patients were infected with COVID-19. [Table: see text]
FORTITUDE: Results of a phase 1a study of the novel transgene-armed and tumor-selective vector NG-350A with and without pembrolizumab (pembro).
Authors: Rosen Lee S. , Camidge D. Ross , Khalil Danny , Lillie Thomas , Carter Jo , Krige David , Davies Jessica , Miles David , Patel Minesh , Evilevitch Vladimir , Prieto González-Albo Isabel , Champion Brian , Naing Aung 
Published: June 2022

2559 Background: Stimulating CD40 may support anti-cancer immune responses; however, on-target toxicity limits systemic dosing. NG-350A is a tumor-selective and blood stable adenoviral T-SIGn vector expressing a potent fully human IgG agonistic anti-CD40 antibody (mAb). NG-350A was designed to selectively deliver anti-CD40 to multiple tumor sites via IV delivery, driving immunological tumor re-engineering while avoiding systemic toxicity. We report results from a first-in-human trial after completion of enrollment. Methods: FORTITUDE (NCT03852511) is a phase 1 study of NG-350A ± pembro in patients (pts) with metastatic/advanced epithelial tumors. NG-350A monotherapy (mTx) was dose-escalated in separate intratumoral (IT; increasing numbers of doses) or IV (one cycle; three increasing dose levels) cohorts. IV NG-350A + pembro (200 mg Q3W for ≤8 cycles) was then assessed. Results: As of Jan 2022, 28 heavily pre-treated pts had received NG-350A, either as IT mTx (n=9; two dose levels), IV mTx (n=16; IV dose levels 1, 3 & 4) or IV + pembro (n=3; IV dose level 2). The MTD of NG-350A ± pembro was not reached, with no DLTs at the highest IT and IV dose levels. The safety profile of NG-350A was consistent with acute reactions to viral particles and asymptomatic aPTT prolongations (Table). No systemic CD40 transgene protein was detected at any dose level and the only SAE to occur in >1 pt was pneumonia. No objective responses were observed; however, 3/6 patients treated with NG-350A mTx at IV dose level 4 achieved stable disease (dose not yet tested with pembro). Dose-dependent specific increases in serum IL-12, IFNγ and IL-17a were detected in pts treated with IV NG-350A mTx from ̃Wk 2. Increases were sustained at ≥5x baseline levels 7 wks after dosing in the majority of evaluable pts treated at higher IV dose levels. These responses did not occur with IT dosing (or in prior studies with an unarmed vector); further follow-up is ongoing for NG-350A + pembro. IV NG-350A also led to the expansion of T cell clones in blood; most of these were newly detected. Conclusions: NG-350A ± pembro was well-tolerated, with no evidence of CD40-related toxicity. NG-350A IV mTx led to specific and sustained cytokine responses consistent with the MoA of the encoded anti-CD40 Ab. Peak cytokine elevations were typically higher than reported with systemic anti-CD40 Abs, suggesting NG-350A can drive local immunological tumor changes while avoiding systemic toxicity. A further trial (FORTIFY, NCT05165433) will continue dose-escalation of NG-350A + pembro to identify a dose level for efficacy assessments. Clinical trial information: NCT03852511. [Table: see text]
A novel polymeric peptide delivery platform and association with targeted co-delivery of antigens and STING agonists with antitumor immune response.
Authors: Wang Max Mu , Choi Mi Ran , Zhang Bin , Gianneschi Nathan 
Published: June 2022

2564 Background: Use of tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, challenges remain in delivering subunit vaccine components in a coordinated fashion to elicit antitumor immune responses. To overcome these, we developed rationally designed vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics that allow for sustained/targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing a model melanoma antigen were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide), degrees of polymerization, and inclusion/exclusion of Oligo(ethylene glycol) (OEG) side chains. In vitro uptake and functional assays using gp100-specific T Cells were conducted with fluorescently-labeled and non-labeled polymers respectively. In vivo experiments were done using a B16F10 murine melanoma tumor model over-expressing gp100. Ability of PLPs to co-deliver immunomodulatory compounds was tested by electrostatically coupling a small molecule STING agonist 2’3’ cGAMP which formed stable nanostructures. The optimized construct was also tested in an OVA system to prove generalizability. Results: Conjugating peptide antigens using a cleavable disulfide linkage, which reduces intracellularly in antigen presenting cells (APCs), resulted in increased endosomal localization and efficacy. Incorporating a diluent amount of OEG side chains increased resistance to enzymatic degradation while improving bioactivity and uptake by APCs. In vivo studies using PLPs conjugated with gp100 resulted in significant increases in survival time and reduced tumor burden in B16 melanoma. Increasing the DP, and therefore the density of antigen side chains, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING-PLP complexes showed significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p < 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which otherwise diffuses rapidly away from the injection site. OVA-PLPs behaved similarly in their cognate system but showed no activity when tested on gp100-specific cells and vice versa demonstrating antigen-specificity. Conclusions: This work validates the potential of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.