bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5195: Humanized CD3E,D,G mice: An ideal model for efficacy study of CD3-bispecific antibodies
Authors: Yang xiaoliu , Ju cunxiang , zhang mingkun , zhao jing 
Published: June 2022

Abstract
CD3-targeting bispecific antibodies (CD3 bsAb) are designed to simultaneously bind to T cells and tumor cell antigens, leading to T-cell activation, proliferation, and tumor cell death. To create a better animal model for studies of CD3-TCBs, we developed the BALBc-hCD3EDG model by gene editing technology, Briefly, a large human genomic fragment containing CD3E,CD3D,CD3G as well as regulatory elements was introduced into the BALBc mouse genome and animals carrying human CD3E,D,G integration were selected to establish the new strain. The BALBc-hCD3EDG mice have a normal immune system and successfully express human CD3E,CD3D,CD3G on the T cell surface. As expected, cytotoxicity of activity T cells by redirecting with CD3-CD20 bsAb was observed in in vitro T cell-mediated killing assays using an A20 cell expressing human CD20. Furthermore, the growth of subcutaneously engrafted CT26 and hCD20-A20 tumors in BALBc-hCD3EDG mice, was strongly inhibited by CD3-TCB antibody treatment. In conclusion, the CD3EDG humanized mice are ideal models for preclinical studies of bispecific antibodies and other immunotherapies.
Citation Format: xiaoliu Yang, cunxiang Ju, mingkun zhang, jing zhao. Humanized CD3E,D,G mice: An ideal model for efficacy study of CD3-bispecific antibodies [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 5195.
Abstract 5200: The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI)
Authors: Kim Hyeonseon , Lee Yeun Ho , Song Chiwoo , Kim Leeseul , Kim Min Jeong , Choi Horyun , Kim Jinah , Chae Young Kwang 
Published: June 2022

Abstract
Background: HPD is an unexpected rapid acceleration of tumor growth reported for patients treated with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinical and genetic risk factors.
Method: A total of 203 patients with NSCLC who received ICI at Northwestern Memorial Hospital during 2008-2020 were included. Tumor growth kinetics (TGK) on immunotherapy and TGK pre-immunotherapy were collected and TGK ratio (TGKR) was calculated. HPD was defined as TGKR≥2.
Result: HPD was observed in 16% (n=33) of patients. HPD was significantly associated with high ECOG (3-4 vs 1-2) [OR = 4.52, 95% CI = 1.31 to 16.29, P = 0.01], presence of bone metastasis [OR = 2.51, 95% CI = 1.10 to 5.28, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, 95% CI = 1.24 to 5.81 P = 0.01], thrombocytosis (platelet count &gt;450k) [OR = 5.31, 95% CI = 2.07 to 14.70, P=0.0003], and treatment with PD-L1 inhibitor vs PD-1 inhibitor [OR = 2.14, 95% CI= 0.97 to 4.68, P= 0.068]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, 95% CI = 0.13 to 0.86, P = 0.01], ICI combined with chemotherapy vs ICI monotherapy [OR = 0.24, 95% CI = 0.055 to 0.97, P=0.04], and positive TTF-1 expression [OR = 0.46, 95% CI = 0.21 to 1.02, P=0.057]. HPD was not associated with histology of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma), age(&lt;70, ≥70), sex, smoking history, number of metastatic lesions (&lt;3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, and TNM staging.
Conclusion: The incidence of HPD in NSCLC treated with ICI was consistent with current literature. High NLR and platelet count are suggestive of an immunosuppressive environment that could contribute to the rapid growth of tumors. To our knowledge, this is the first study to report an inverse correlation of PD-L1 expression and TTF-1 expression with HPD. The strength of our study lies in a large number of patients. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted.
Citation Format: Hyeonseon Kim, Yeun Ho Lee, Chiwoo Song, Leeseul Kim, Min Jeong Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI) [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 5200.
Abstract 5207: Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity
Authors: Lucarini Valeria , Melaiu Ombretta , D'Amico Silvia , Pastorino Fabio , Tempora Patrizia , De Ninno Adele , Businaro Luca , Ponzoni Mirco , Locatelli Franco , Fruci Doriana 
Published: June 2022

Abstract
Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we employed a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitise two mouse models of neuroblastoma (NB) sparsely infiltrated by T cells to the host antitumor immune response. Using multiple in vitro, ex vivo, and in vivo approaches, we found that mitoxantrone treatment curbed NB growth and promoted tumor regression when combined with TGFβ and PD-1 blockade in aggressive NB models. This combined immunotherapy strategy resulted in the enrichment of a variety of both innate and adaptive immune cells into the TME, and the concomitant production of inflammatory chemokines involved in remodelling the tumor’s immune landscape. Mitoxantrone in combination with TGFβ and PD-1 blockade could be used to reshape the functional repertoire of intratumoral immune cells, restoring the entire immune cell cycle and overcoming the immunosuppressive microenvironment of aggressive NB.
Citation Format: Valeria Lucarini, Ombretta Melaiu, Silvia D'Amico, Fabio Pastorino, Patrizia Tempora, Adele De Ninno, Luca Businaro, Mirco Ponzoni, Franco Locatelli, Doriana Fruci. Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity [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 5207.
Abstract 521: The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma
Authors: Esser Laura Kristin , Branchi Vittorio , Shaker Farhad , Simon Adrian Georg , Stephan Carsten , Kristiansen Glen , Buness Andreas , Schorle Hubert , Toma Marieta I. 
Published: June 2022

Abstract
Introduction: The E3 ubiquitin ligase Parkin has been described in several cancer entities, including clear cell renal cell carcinoma (ccRCC). Decreased Parkin expression is associated with poor prognosis. We aimed to clarify the biological role of Parkin in ccRCC and to evaluate its expression in a clinically characterized renal cancer cohort.
Methods: We analyzed cell lines and clinically annotated patient material with qPCR (n=63), immunohistochemistry (n=262), LC-mass spectrometry and performed functional analyses in cell line models.
Results: We found that overexpression of Parkin results in a less aggressive phenotype in the clear cell renal cell carcinoma cell line 786-O indicated by lower migration and invasion. Mass spectrometry revealed decreased levels of several proteins in Parkin expressing cells. One of these proteins was cyclin kinase subunit 2 (CKS2). The introduction of a C431S mutation in the catalytic domain of the Parkin gene abolished the effect of decreased migration. In addition, knockdown of CKS2 in cells lacking Parkin caused decreased migration suggesting that the effect of Parkin is CKS2 mediated. Furthermore, the correlation of CKS2 and tumor grading is highly significant and high levels of CKS2 are associated with shorter survival times.
Conclusions: Parkin plays a major role in ccRCC biology, regulation cell migration and invasion, possibly exerted by CKS2 signaling. In consequence CKS2 appears to be an interesting prognostic biomarker in clear cell renal cell carcinoma and might also serve as a new therapy target.
Citation Format: Laura Kristin Esser, Vittorio Branchi, Farhad Shaker, Adrian Georg Simon, Carsten Stephan, Glen Kristiansen, Andreas Buness, Hubert Schorle, Marieta I. Toma. The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma [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 521.
Abstract 5231: Case report: dramatic response to Crizotinib in a patient with synchronous multiple primary lung cancer positive for a novel ARL1-MET fusion
Authors: Ma Qing , Kong Lingping , Zhong Diansheng 
Published: June 2022

Abstract
Background: With the use of high-resolution chest imaging system, an increasing number of lung cancer patients are being diagnosed with multiple primary lung cancer (MPLC). Although surgery is considered as the first choice of treatment for early MPLC, targeted therapy is essential in the management of unresectable MPLC. To date, the driver oncogenes reported in the patients with MPLC are limited, and MET fusion has not yet been reported in MPLC.
Case presentation: In this case, we reported a female patient with simultaneous MPLC (sMPLC). A novel ARL1-MET fusion was detected in her right lung tumor tissues using next-generation sequencing (NGS). The patient achieved about 5-month progressive-free survival (PFS) after receiving Crizotinib for the unresectable right lung malignancies.
Conclusion: To the best of our knowledge, this case provided the first clinical evidence that the novel ARL1-MET fusion might be an actionable mutation in sMPLC.
Citation Format: Qing Ma, Lingping Kong, Diansheng Zhong. Case report: dramatic response to Crizotinib in a patient with synchronous multiple primary lung cancer positive for a novel ARL1-MET fusion [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 5231.
Abstract 5250: Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer
Authors: Lv Huifang , He Yunduan , Nie Caiyun , Chen Beibei , Wang Jianzheng , Xu Weifeng , Zhao Jing , Chen Xiaobing , Zhang Junling 
Published: June 2022

Abstract
Objective: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in irinotecan metabolism. However, the relationship between UGT1A1 genotype and the safety and efficacy of irinotecan monotherapy in the treatment of Chinese advanced gastric cancer remains unclear.
Methods: A total of 110 patients were enrolled. Intravenous irinotecan was administered every 3 weeks. Irinotecan dose was selected according to the polymorphism of UGT1A1 gene, which was divided into 3 groups: UGT1A1*6 wild-type (GG type): 125mg/m2, d1, d8; UGT1A1*6 mutant heterozygosity (GA type) 100mg/m2, d1, d8; UGT1A1*6 homozygosity mutation (AA type) 75mg/m2, d1, d8 or paclitaxel 125mg/m2, d1, d8. UGT1A1 genotypes were determined by direct sequencing or next-generation sequencing of genomic DNA extracted from peripheral blood.
Results: Among 110 patients of the subjects, the genotypes of UGT1A1*28 were wild-type in 78 patients (70.91%), mutant heterozygosity in 28 (25.45%) and mutant homozygosity in 4 (3.64%). UGT1A1*6 were GG in 67 cases (60.91%), GA in 35 cases (31.82%), and AA in 8 cases (7.27%). There were two heterozygous mutations in 3 patients, and no homozygous mutation was detected. A total of 10 cycles of irinotecan were administered, with a median of five cycles per patient. There was no significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*28 genotypes (P&gt;0.05), while there was significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*6 genotypes (P&lt;0.05). The dose intensity of irinotecan was different in patients with different subtypes of UGT1A1*6 gene, and the dose intensity of heterozygous mutant patients was lower than that of wild-type patients. However, there were no significant differences in PFS and OS among patients with different subtypes after dose adjustment and program adjustment (P&gt;0.05).
Conclusion: UGT1A1*6 gene polymorphism was significantly associated with diarrhea and neutropenia induced by irinotecan. The safety and effectiveness of antitumor therapy might be significantly improved by individualized drug administration according to the results of UGT1A1*6 gene polymorphism.
Citation Format: Huifang Lv, Yunduan He, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Jing Zhao, Xiaobing Chen, Junling Zhang. Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric 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 5250.
Abstract 5258: Mortality patterns among cancer survivors receiving care in dedicated survivorship clinics
Authors: Ramsey Katherine R. , Chapman Patricia H. , Palos Guadalupe R. , Rodriguez Maria A. 
Published: June 2022

Abstract
Introduction: The number of deaths occurring among cancer survivors continues to be an outcome of concern. Our survivorship clinics provide risk stratification care for patients who have completed their curative treatment and are seen annually in a site-specific clinic. Here we describe mortality rates among adult patients receiving care in eleven site-specific survivorship clinics.
Procedures: We conducted an analysis of 29,418 adult patients seen in our survivorship program from 2008-2021. Medical records were reviewed and categorized by each survivorship clinic. Eligibility criteria were: patients ≥18, treated for curative intent, completed their primary course of treatment, past the highest risk of recurrence, and transitioned based on site-specific survivorship algorithms. Descriptive statistics summarize the results.
Results: There were 26475 survivors alive and 2943 deaths (Table 1). Of those alive, the greatest number were diagnosed with breast, genitourinary, and gastrointestinal malignancies. Death rates ranged from 2% to 38%, with the highest percent in stem cell transplant, head and neck, and gynecology malignancy survivors. 29% of deceased patients had died within one year of their transition from oncology care to survivorship clinics.
Conclusions: Our results indicate differences in mortality risk among different cancer survivors; those who received transplants or were diagnosed with gynecologic or head/neck cancers had higher death rates. Survivors in these groups have short and long-term health risks which may require more proactive care. Current analyses are underway on the cause of death among patients who passed away within the first year of the transition to survivorship.
Table 1. Total Number of Patients Seen by Clinic, Alive or Deceased Status, and Average Years Between First Appointment and Death (N=29418) Clinic Total No. No. Alive Percent Alive No. Deaths PercentDeaths Avg Years from First Appt to Death Breast 11972 11219 94% 753 6% 4 GI 837 787 94% 50 6% 3 GU 4264 3952 93% 312 7% 4 Gyn 1284 1175 91% 109 8% 4 Head & Neck 2763 2482 90% 281 10% 3 Lymphoma 759 707 93% 52 7% 4 Melanoma 1234 1174 95% 60 5% 3 Sarcoma 87 85 98% 2 2% 1 Stem Cell Transplant 3141 1917 61% 1224 39% 1 Thoracic 489 461 94% 28 6% 2 Thyroid 2588 2516 97% 72 3% 4
Citation Format: Katherine R. Ramsey, Patricia H. Chapman, Guadalupe R. Palos, Maria A. Rodriguez. Mortality patterns among cancer survivors receiving care in dedicated survivorship clinics [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 5258.
Abstract 527: A streamlined workflow for liquid biopsy extraction and highplex digital PCR analysis using the Maxwell® RSC system and 6-color Crystal Digital PCR™
Authors: Jovelet Cécile , Remy Myrtille , Menanteau Mylene , White Doug , Horejsh Douglas , Mallory Allison 
Published: June 2022

Abstract
Circulating cell free DNA (cfDNA) extracted from liquid biopsy samples have become established sample types for characterizing oncology targets. Currently, there are several extraction protocols and genomic platforms for researchers to select when interrogating genetic information.
The focus of this work was to identify a flexible method for sample extraction that seamlessly integrates into a straightforward and sensitive genetic analysis workflow from plasma samples. Here, we present a workflow combining the Maxwell RSC system for automated cfDNA extraction and Crystal Digital PCR on the naica system for ultrasensitive high-plex detection from liquid biopsy samples of EGFR mutations in non-small cell lung cancer (NSCLC) and PIK3CA mutations and HER2 amplification in breast cancer.
By bridging sample extraction with the Maxwell RSC system and high-plex digital PCR with the 6-color naica® system, we detected with high sensitivity and precision 32 common and rare somatic EGFR mutations in exons 18, 19, 20, and 21, representing more than 90% of EGFR mutations described in NSCLC. Furthermore, following the same extraction and sample testing workflow, we simultaneously detected a set of PIK3CA mutations and HER2 amplification from cfDNA samples. This proof-of-concept workflow creates the foundation for further development of streamlined sample-to-answer protocols that will better assist cancer researchers across the biomarker testing landscape.
Citation Format: Cécile Jovelet, Myrtille Remy, Mylene Menanteau, Doug White, Douglas Horejsh, Allison Mallory. A streamlined workflow for liquid biopsy extraction and highplex digital PCR analysis using the Maxwell® RSC system and 6-color Crystal Digital PCR™ [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 527.
Abstract 5294: MDX-124, a novel annexin-A1 antibody, induces significant anti-cancer activity in multiple preclinical models
Authors: Dempsey Fiona C. , Al-Ali Hussein , Crichton Scott J. , Fabian Charlene , Pepper Chris , Qian Bin-Zhi , Li Xue-Feng , Parris Christopher N. 
Published: June 2022

Abstract
Annexin-A1 (ANXA1) is secreted from both cancer and immune cells in response to several physiological stimuli and modulates cellular functions through interactions with formyl peptide receptors (FPR1/2). Overexpression of ANXA1 has been observed in multiple cancers, including triple-negative breast (TNBC), colorectal, lung, pancreatic, gastric and prostate, and correlates with poor prognosis and decreased overall survival. ANXA1 has also been shown to promote cancer cell proliferation, angiogenesis, migration and drug resistance, and to modulate the tumor microenvironment. MDX-124 is a novel humanized antibody targeting ANXA1. Previously we presented data demonstrating its significant anti-proliferative activity. Here we provide further data on the mechanism of action of MDX-124, notably its impact on tumor growth, cell cycle arrest and migration in several preclinical cancer models. Incubation of pancreatic (BxPC-3), lung (A549) and TNBC (MDA-MB-231) cancer cell lines with MDX-124 for 24 h decreased the proportion of cells in S-phase by up to 18.3% with a concomitant increase in G1 phase of up to 33.5% versus untreated cells. This effect occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest. After 72 h incubation with MDX-124, the migratory ability of gastric (AGS), prostate (PC-3), TNBC (MDA-MB-231), lung (A549), pancreatic (MIA PaCa-2) and colorectal (LoVo) cancer cells was significantly reduced in a dose-dependent manner when compared to untreated controls. Proteomic analysis following incubation of MDX-124 with a panel of cancer cell lines for 72 h demonstrated substantial alterations in the level of expression and phosphorylation of multiple key oncogenic proteins. In the MycCaP-Bo syngeneic model of bone metastatic prostate cancer, mice treated with the murine analog of MDX-124 (10 mg/kg, BIW) had a 52% reduction in mean tumor growth after 14 days compared to isotype control treated mice. In conclusion, our data indicate that targeting ANXA1 with MDX-124 inhibits key tumorigenic processes in several clinically challenging cancer indications. MDX-124 therefore provides an innovative approach to cancer therapy. Medannex initiated a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies known to overexpress ANXA1.
Citation Format: Fiona C. Dempsey, Hussein Al-Ali, Scott J. Crichton, Charlene Fabian, Chris Pepper, Bin-Zhi Qian, Xue-Feng Li, Christopher N. Parris. MDX-124, a novel annexin-A1 antibody, induces significant anti-cancer activity in multiple preclinical models [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 5294.
Abstract 5296: Poly(ADP-ribose) polymerase-1 expression is a good survival marker in pancreatic cancers, unlike other solid cancers
Authors: Yim Kwangil , Thakur Nishant , Alam Mohammad Rizwan , Abdul-Ghafar Jamshid , Chong Yosep , Seo Kyung Jin , Shin Ok Ran 
Published: June 2022

Abstract
Purpose: Poly(ADP-ribose) Polymerases-1 (PARP-1) is well known as poor survival factor in various solid cancers and its inhibitors have shown promising results in clinical trials. However, in pancreatic ductal adenocarcinoma (PDAC), there is only one study with good prognostic result. We assessed the prognostic significance of PARP-1 in PDAC
Methods: From 1998 to 2020, 194 patients with radical surgery for PDAC were enrolled in Yeouido St. Mary’s hospital (n = 84) and Uijeongbu St. Mary’s hospital (n=110). After making tumor microarray, PARP-1 immunohistochemistry was conducted and we analyzed H score with image analyzer (QuantCenter, 3DHistech, Budapest, Hungary).
Results: High expression of PARP1 (OS: p = 0.004, CSS: p = 0.007, DFS: p &lt; 0.001) was good survival factor in univariate analysis. Old age (OS: p = 0.018, CSS: p = 0.041, DFS: p = 0.050 ), high stage (OS: p = 0.004, CSS: p = 0.009, DFS: p = 0.817), lymphatic invasion (OS: p &lt; 0.001, CSS: p &lt; 0.001, DFS: p = 0.001), venous invasion (OS: p &lt; 0.001, CSS: p &lt; 0.001, DFS: p = 0.109), perineural invasion (OS: p &lt; 0.001, CSS: p &lt; 0.001, DFS: p &lt; 0.001) and high grade tumor differentiation (OS: p = 0.005, CSS: p = 0.003, DFS: p = 0.001 ) was poor survival factor in log rank test. In multivariate analysis, PAPR1 was independent good survival factor (OS: p = 0.002, CSS: p = 0.005, DFS: p &lt; 0.001).
Conclusion: Our study revealed that PARP1 expression was good survival factor in PDAC unlike other solid cancers. In our observation, studies with larger datasets or on the mechanism of PARP1 in PDAC are necessary in order to use PARP inhibitor in PDAC.
Citation Format: Kwangil Yim, Nishant Thakur, Mohammad Rizwan Alam, Jamshid Abdul-Ghafar, Yosep Chong, Kyung Jin Seo, Ok Ran Shin. Poly(ADP-ribose) polymerase-1 expression is a good survival marker in pancreatic cancers, unlike other solid cancers [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 5296.