bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5136: Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib
Authors: Kuronishi Megumi , Ozawa Yoichi , Kimura Takayuki , Kato Yu 
Published: June 2022

Abstract
Lenvatinib is a multiple receptor tyrosine kinase inhibitor and an angiogenesis inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. In our previous study, we reported that human xenograft tumors sensitive to lenvatinib showed higher microvessel density (“MVD (IHC)”) than relatively resistant tumors in immunohistochemistry (IHC). Although MVD (IHC) is a potential indicator to predict antitumor activity of lenvatinib, available IHC data are limited. Here, we investigated a novel gene expression signature (MVD gene score) calculated from RNA-sequencing (RNA-seq) data that reflects MVD (IHC) and antitumor effect of lenvatinib.
Tumor tissues were collected from 12 mouse syngeneic tumor models followed by RNA-seq. We also stained CD31 in the same tumors and calculated MVD (IHC) score by dividing the number of CD31 positive blood vessels by tumor area. Genes that met the following criteria were selected for MVD gene score calculation: (1) genes that are specifically expressed on endothelial cell cluster in in-house single cell RNA-seq data using Hepa 1-6 mouse hepatocellular carcinoma tumor tissues; (2) well-known angiogenesis markers from literature or genes whose expression show significant correlation with MVD (IHC) in mouse syngeneic tumor models. MVD gene score was calculated as the average of logarithm transformed gene expression values. In order to examine applicability of MVD gene score, we compared MVD (IHC) and MVD gene score to lenvatinib antitumor activities on mouse syngeneic tumors.
We measured MVD (IHC) and computed MVD gene score from RNA-seq data using matched tumor tissues of 12 mouse syngeneic models. MVD gene score was correlated with MVD (IHC). As reported, lenvatinib sensitive tumor models showed higher MVD (IHC) score. They also showed higher MVD gene score calculated from RNA-seq data.
Our newly developed MVD gene score has a potential to predict the antitumor activity of angiogenic inhibitors such as lenvatinib using RNA-seq data in tumor samples. Further validation study is ongoing using various human tumor samples.
Citation Format: Megumi Kuronishi, Yoichi Ozawa, Takayuki Kimura, Yu Kato. Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5136.
Abstract 514: Correlation of sTNFR2 elevation and disease progression in cutaneous T cell lymphomas
Authors: Lee Amanda , Kim Youn , Khodadoust Michael , Faustman Denise L. 
Published: June 2022

Abstract
Tumor necrosis factor receptor 2 (TNFR2), a membrane receptor that is a part of the tumor necrosis factor (TNF) superfamily and one of two receptors that can bind to TNF-α, has been emerging in recent years as a promising cancer immunotherapy target. TNFR2 is commonly overexpressed in cancer cells and in the tumor microenvironment. It is also a key receptor in immune evasion, due to its abundance on the most immunosuppressive subset of Treg cells (CD4+Foxp3+), as well as its role in driving proliferation of regulatory T cells (Tregs) and tumor cells via activation of the nuclear factor kappa B (NF-κB) pathway. In environments with high cell proliferation and high surface densities, TNFR2 can be cleaved and shed as serum soluble TNFR2 (sTNFR2). In human cancers, high sTNFR2 has recently been associated with poor prognostic outcomes in colon cancer, esophageal cancer, endometrial cancer and non-Hodgkin’s lymphomas. Elevated sTNFR2 is also potentially associated with poor prognostic outcomes in cutaneous T cell lymphomas (CTCLs), a diverse group of lymphomas primarily composed of mycosis fungoides (MF) and Sézary syndrome (SS), with symptoms that primarily manifest in the skin. Given sTNFR2’s accessibility in serum and association with cancer prognosis, we investigated its role as a potential biomarker for MF and SS prognosis. We also evaluated whether the CTCL tumor type is mechanistically being driven by very suppressive Tregs and tumor cells with this oncogene. In our study, we measured baseline sTNFR2 levels from 31 serum samples across different cancer stages (Stage I-IV) of MF and SS in either treatment-naïve subjects or subjects free of any treatments for ≥3 months. Our initial data shows that sTNFR2 values correlate with levels of blood disease and increase as the cancer advances. These findings strengthen the possibility of using sTNFR2 as a biomarker in MF and SS and also support the possible mechanistic role of TNFR2 in disease pathogenesis. Analysis of the same serum samples for sTNFR1, a non-specific marker of inflammation and renal failure, confirm that the increases are exclusive to sTNFR2 and can indeed be attributed to MF and SS, rather than to non-specific inflammation. Further studies following these patients’ responses to their treatment plans (i.e., mogamulizumab, romidepsin) will help elucidate the potency of sTNFR2 in predicting response to treatment and cancer burden.
Citation Format: Amanda Lee, Youn Kim, Michael Khodadoust, Denise L. Faustman. Correlation of sTNFR2 elevation and disease progression in cutaneous T cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 514.
Abstract 5166: Blood-based biomarker analysis for predicting efficacy of definitive concurrent chemoradiotherapy and durvalumab consolidation in patients with unresectable locally advanced non-small cell lung cancer
Authors: Park Cheol-Kyu , Park Hwa-Kyung , Oh Hyung-Joo , Cho Hyun-Ju , Oh In-Jae , Kim Young-Chul 
Published: June 2022

Abstract
Background: This study aimed to investigate the feasibility of using circulating tumor cells (CTCs) and peripheral blood cells (PBCs) as biomarkers for predicting the efficacy of concurrent chemoradiotherapy (CCRT) and durvalumab consolidation (DC) in patients with locally advanced non-small cell lung cancer (NSCLC).
Methods: We recruited patients diagnosed with unresectable stage III NSCLC who received definitive CCRT between March 2020 and March 2021. DC was permitted in patients who did not progress after CCRT and tumor PD-L1 ≥1%. Blood samples were collected before (C0) and after CCRT (C1) to calculate PBC counts and analyze CTCs. CTCs, isolated using CD-PRIME࣪ system, exhibited EpCAM/CK+/CD45− phenotype in BioViewCCBS࣪.
Results: A total of 50 patients were enrolled and 23 patients received DC. The median duration of follow-up was 16.3 months, and the median progression-free survival (PFS) was not significantly different between patients with and without DC (13.1 vs. 13.5 months; p=0.355). In overall, patients with higher platelets (PLThi, &gt;252x103/uL) at C1 had worse median PFS than those with lower platelets (PLTlo, ≤252x103/uL) (5.9 vs. 15.1 months; p&lt;0.001). In DC group, patients with residual CTC clusters after CCRT (C1) had worse median PFS than those without detectable CTC cluster (9.5 vs. not reached; p=0.034). In multivariate analysis, PLThi at C1 was an independent factor for PFS (hazard ratio [HR] 4.12, 95% confidence interval [CI] 1.77-9.61; p=0.001), and patients with DC who had PLThi and residual CTC clusters at C1 showed the worst PFS (2.6 months, HR 44.40; p=0.001), even worse than those without DC who had PLThi (5.9 months, HR 15.65; p=0.002).
Conclusions: Comprehensive analysis of CTC and PBC counts before and after CCRT, especially CTC clusters and platelets at C1, demonstrated they might be biomarkers for predicting survival. This finding could aid in risk stratification of patients with unresectable stage III NSCLC who are eligible for DC after definitive CCRT.
Citation Format: Cheol-Kyu Park, Hwa-Kyung Park, Hyung-Joo Oh, Hyun-Ju Cho, In-Jae Oh, Young-Chul Kim. Blood-based biomarker analysis for predicting efficacy of definitive concurrent chemoradiotherapy and durvalumab consolidation in patients with unresectable locally advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5166.
Abstract 5167: Enhanced isolation of circulating tumor cells from leukapheresis material enabled by Akadeum microbubbles
Authors: Grimley Edward , Roussey Jon , Ku Chia , Livi Carolina , Petlakh-Co Nadia , Wegner Casey , McNaughton Brandon H. 
Published: June 2022

Abstract
Circulating tumor cells (CTCs) have shown incredible promise in clinical and diagnostic applications. CTC-based liquid biopsies can aid in earlier diagnosis, identify the stage of disease, guide therapeutic aggressiveness, and be used to monitor response to treatment. While CTCs hold incredible promise in these areas, there are inherent limitations that hinder realization of the full potential of CTC-based liquid biopsy tests. The rarity of CTCs is one of the most significant factors limiting clinical utility. A standard 10-mL blood draw may simply not contain the number of CTCs needed to yield meaningful results. One method to analyze greater blood volume is by leukapheresis. While clinical leukapheresis can enrich mononuclear cells, including CTCs, from almost the entire volume of a patient’s blood, most downstream CTC enrichment methods are not compatible with leukapheresis material as a starting sample. To overcome these compatibility issues, Akadeum Life Sciences has developed a novel and proprietary Buoyancy Activated Cell Sorting (BACS™) microbubble platform that can be functionalized to selectively enrich biological samples for target cell populations using a fast, easy protocol that is exceptionally gentle on delicate cells of interest. Akadeum’s low-density BACS microbubbles are mixed into the sample where they quickly engage their targets and naturally float them to the surface for removal. This straightforward approach is elegant in simplicity and powerful in application, offering some of the fastest and most gentle isolations available. In this study, we demonstrate a protocol for the depletion of white blood cells (WBCs) & residual red blood cells (RBCs) from leukapheresis material via microbubbles. This novel protocol reveals a &gt; 99% combined depletion of residual RBCs and WBCs, providing over 120-fold enrichment of tumor cells. Importantly, this protocol delivers exceptional yield with &gt; 99% retention of the target tumor cells. This optimized workflow delivers an enriched and viable population of untouched and unaltered CTCs for downstream use.
Citation Format: Edward Grimley, Jon Roussey, Chia Ku, Carolina Livi, Nadia Petlakh-Co, Casey Wegner, Brandon H. McNaughton. Enhanced isolation of circulating tumor cells from leukapheresis material enabled by Akadeum microbubbles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5167.
Abstract 5169: Sentinel lymph node gene expression signature predicts survival outcome in cutaneous melanoma
Authors: Karapetyan Lilit , Gooding William , Yang Xi , Knight Andrew , Li Aofei , Sander Cindy , Panelli Monica , Storkus Walter J. , Tarhini Ahmad A. , Kirkwood John M. 
Published: June 2022

Abstract
Background: Sentinel lymph node status is an important prognostic factor for melanoma progression. We sought to develop a sentinel lymph node gene expression signature score predictive of disease progression in patients with cutaneous melanoma.
Methods: Cases were retrieved from University of Pittsburgh protocol “Sentinel Node and Non-Sentinel Lymph Nodes (SLN and non-SLN) Procurement from Melanoma Subjects for Molecular Profiling.” Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with progression-free survival (PFS) were selected and a penalized regression function was used to select genes with a non-zero coefficient. A risk score was calculated from a 12 gene signature. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and PFS.
Results: In total, 45 patients were included [female=18 (40%), median age (range)= 56 (16-81) years]. The median Breslow thickness (IQR) was 4.1 (3.3-6.0) mm, ulceration was present in 29 (67%) cases, and 25 (56%) lesions had nodular histology. Among patients, 23 (51%) had a positive SLN via H&E. Twenty-one (46.7%) patients developed disease recurrence/progression with a median follow-up of 8.3 years. The median time to progression was 9.6 years. Among the top 25 genes, 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, ZNF223, PDE6G, CXCL3, CHRFAM7A, HLA-DRB-decreased risk, DCTN1, ASPSCR1, HEXIM1-increased risk). A 12-gene signature score was significantly associated with PFS (p&lt;0.0001) and produced a bootstrap cross-validated C index of 0.888. Stratifying by SLN status the gene signature risk score remained highly significant (p&lt;0.0001). In univariate analysis, Breslow thickness (HR=1.41), presence of ulceration (HR=3.61), SLN positivity (HR=2.50), and acral-lentiginous histology compared to nodular (HR=4.07) were each significantly associated with PFS (all p&lt;0.05). After simultaneously adjusting for all of these factors plus the gene signature, the 12-gene score remained a significant predictor for PFS (p&lt;0.0001).
Conclusion: A SLN 12-gene signature risk score is associated with melanoma progression regardless of SLN status and can be used as a prognostic factor for PFS of patients. External validation of the gene signature is warranted.
Citation Format: Lilit Karapetyan, William Gooding, Xi Yang, Andrew Knight, Aofei Li, Cindy Sander, Monica Panelli, Walter J. Storkus, Ahmad A. Tarhini, John M. Kirkwood. Sentinel lymph node gene expression signature predicts survival outcome in cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5169.
Abstract 517: Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence
Authors: Yuen Kit L. , Wu Chia-Hao , Silvers Christopher R. , Steinmetz Alexis R. , Miyamoto Hiroshi , Messing Edward M. , Lee Yi-Fen 
Published: June 2022

Abstract
INTRODUCTION AND OBJECTIVE: High recurrence rates found in non-muscle invasive bladder cancer (NMIBC) pose a financial and psychological burden for patients. We demonstrated that bladder cancer (BC) cells release protein disulfide isomerase (PDI), a redox-regulated ER-resident protein, via extracellular vesicles (EVs) when experiencing high levels of ER stress for their own survival. Chronic exposure to PDI-enriched BC EVs induced malignant transformation in recipient non-transformed cells. We hypothesized that the dynamic redox state in BC cells determines PDI cellular localization and tumors with elevated PDI preferentially incorporate PDI into EVs for removal. Furthermore, PDI expression levels and subcellular localization in tumors from NMIBC patients may predict NMIBC recurrence.
METHODS: Retrospective chart review identified 122 patients with newly diagnosed low-grade NMIBC classified into 2 groups: recurrent (N=55) and non-recurrent (N=67) during follow-up period. Formalin fixed paraffin embedded tumor specimens from index transurethral resection of bladder tumor (TURBT) were obtained and a tissue microarray (TMA) was constructed. Immunofluorescent staining of TMA sections was conducted using antibodies against PDI and BiP, an ER stress marker. Stained tissues were photographed and tumor regions in each field were manually masked and confirmed by a genitourinary pathologist. Within each tumor region, total antibody labeling was determined by measuring the mean pixel intensity values with NIH ImageJ/Fiji. Manders coefficient was used to assess the colocalization of epitopes using JACoP plugin in ImageJ.
RESULTS: Tumor tissues from patients that recurred expressed significantly higher levels of PDI and BiP. Moreover, high PDI and BiP expression predicted worse recurrence-free survival. These data suggest that tissues under higher levels of ER stress—as indicated by higher levels of PDI and BiP expression—have a higher risk of recurrence. Significantly higher levels of PDI were detected in non-ER cytosol in recurrent cohort tumors.
CONCLUSIONS: This study provides a novel mechanism for BC recurrence and valuable clinical predictive biomarkers for NMIBC recurrence and progression. Future clinical applications targeting this pathway may be an avenue to prevent NMIBC recurrence.
Citation Format: Kit L. Yuen, Chia-Hao Wu, Christopher R. Silvers, Alexis R. Steinmetz, Hiroshi Miyamoto, Edward M. Messing, Yi-Fen Lee. Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 517.
Abstract 5198: Dynamics of circulating immune cells during chemoradiotherapy in patients with locally advanced non-small cell lung cancer support earlier administration of anti-PD-1/PD-L1 therapy
Authors: Kim Kyung Hwan , Pyo Hongryull , Oh Dongryul , Noh Jae Myoung , Ahn Yong Chan , Yoon Hong In , Lee Jiyun , Park Sehhoon , Jung Hyun-Ae , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Park Keunchil , Ku Bo Mi , Ahn Myung-Ju , Shin Eui-Cheol 
Published: June 2022

Abstract
Background: Chemoradiotherapy (CRT) followed by consolidation immune checkpoint inhibitors (ICIs) significantly improves survival in unresectable locally advanced non-small cell lung cancer (LA-NSCLC). However, the optimal sequence for CRT and ICIs has not yet been established. We investigated the dynamics of peripheral blood immune cells during CRT to determine the best sequence for treatment.
Methods: Peripheral blood samples were prospectively collected pre-treatment, weekly during CRT for 6 weeks, and 1 month post-treatment in 24 patients with LA-NSCLC who received definitive CRT. Immune cell analysis was performed by flow cytometry. Ex vivo PD-1 blockade assays were performed by IFN-γ intracellular cytokine staining.
Results: Lymphopenia was prominently observed during CRT and mostly recovered 1 month post-CRT. Robust proliferation of CD8+ T cells was induced, peaking in the last week during CRT and decreasing post-CRT. The robust proliferation of CD8+ T cells led to an increase in the frequency of CD28-CD57+ replicative senescent and terminally differentiated cells post-CRT. Tumor-reactive CD8+ T cells increased during CRT and peaked in the last week. One month post-CRT, the frequency of tumor-reactive CD8+ T cells decreased and TOXhiTCF1lo terminally exhausted CD8+ T cells significantly increased. Anti-PD-1-induced functional restoration of PD-1+CD8+ T cells was maximized in the last week of CRT and significantly decreased post-CRT.
Conclusions: The findings suggest that earlier administration of PD-1 blockade may be associated with superior efficacy compared to delayed administration after completion of CRT. These findings provide an immunological rationale for optimal timing of combining ICIs with CRT in clinical trials.
Citation Format: Kyung Hwan Kim, Hongryull Pyo, Dongryul Oh, Jae Myoung Noh, Yong Chan Ahn, Hong In Yoon, Jiyun Lee, Sehhoon Park, Hyun-Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Bo Mi Ku, Myung-Ju Ahn, Eui-Cheol Shin. Dynamics of circulating immune cells during chemoradiotherapy in patients with locally advanced non-small cell lung cancer support earlier administration of anti-PD-1/PD-L1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5198.
Abstract 5212: Braf-altered microsatellite-stable metastatic colorectal cancer: A niche for immunotherapy
Authors: Kuan Feng-Che , Shi Chung-Sheng , Wu Yu-Ying , Lin Meng-Hung 
Published: June 2022

Abstract
Background: The successful inhibition of the PD-1/PD-L1 axis and CTLA-4 has opened the era of immuno-oncology, however only a few patients with metastatic colorectal cancer (mCRC) and microsatellite instability (MSI, ~5%) derive survival benefits from these treatments. BRAF genomic alterations, mainly V600 point mutations, comprise 10-15% of cases and have a poorer prognostic phenotype.
Method: The public domain genomic database (via cBioPortal and AACR Project GENIE) was used as an external control to explore the genomic make-up of BRAF-mutated and BRAF-wild mCRC tumors. The Wilcoxon sum rank test was used for the genome-wide association analysis, and the Kaplan-Meier method was used to estimate survival. Besides, clinical observations on extraordinary responses to regorafenib plus nivolumab therapy in two patients with microsatellite stable (MSS) mCRC with BRAF genomic alterations were reported.
Result: The CRC cohort comprised 2,936 patients and the immune checkpoint inhibitor (ICI) treated cohort comprised 1,661 patients, of which 110 (6.6%) were CRC patients. BRAF genomic alterations (CRC versus ICI cohort: 12.4% versus 11.8%, respectively) were significantly associated with POLE and PRKDC gene mutations (p&lt;0.001). The genomic signatures, such as higher mutation count (MC) (log2 [6.54 versus 3], Wilcoxon p&lt;10-10) and lower fraction genome altered (FGA) (log2 [-3.62 versus -2.22], Wilcoxon p=2.08e-9) were similar to that of POLE and PRKDC in the CRC cohort. Also, BRAF genomic alterations are associated with higher mutation counts in not only MSI but MSS cohorts (p=0.033 and p&lt;0.001, respectively). In the ICI cohort, BRAF-altered colorectal tumors were associated with a higher TMB (43.3 versus 7.81, Wilcoxon p=0.016). In the CRC cohort, BRAF-altered tumors were associated with poorer overall survival (median 38.04 versus &gt;80 month, log rank p&lt;0.0001); and in the ICI cohort, BRAF-altered colorectal tumors were associated with a trend of better overall survival after ICI treatment (median &gt;80 versus 15 months, log rank p=0.121)
Conclusion: BRAF-mutated malignancies represent a sub-population of MSS CRC with higher TMB, which could benefit from a combination of regorafenib and nivolumab therapy.
Citation Format: Feng-Che Kuan, Chung-Sheng Shi, Yu-Ying Wu, Meng-Hung Lin. Braf-altered microsatellite-stable metastatic colorectal cancer: A niche for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5212.