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Saito, Akira, Hideyuki Ohzawa, Yuki Kaneko, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Yuki Kimura i in. "Abstract 6379: Dipeptidyl peptidase-4 inhibitor impairs the outcomes of patients with type 2 diabetes mellitus after curative resection for colorectal cancer". Cancer Research 82, nr 12_Supplement (15.06.2022): 6379. http://dx.doi.org/10.1158/1538-7445.am2022-6379.
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Abstract Background: Type2 diabetes mellitus(T2DM) is a risk factor for cancer. Recent studies have shown that DPP-4 inhibitor(DPP-4i) can either promote or suppress cancer progression. However, the detailed mechanisms remain unknown. Here, in this study, we investigated the effect of DPP-4i on tumor microenvironment and its effect on the prognosis of cancer patients. Method: We retrospectively examined the outcome of colorectal cancer (CRC) patients with T2DM who received curative surgery in Jichi Medical University Hospital and asked the impact of DPP-4i intake on their outcome. In addition, we performed immunohistochemistry to examine the phenotypes of TIL, TAM and epithelial-mesenchymal transition (EMT) of cancer cells in surgically removed CRC tissues in 40 CRC patients who had taken DPP-4i and propensity score-matched 40 patients who had not. Results: A total of 1696 patients underwent curative colectomy from April 2010 to March 2020. Among them, 260 patients had T2DM at the time of surgery, and 135 patients had been treated with drugs including DPP-4i. The postoperative disease-free survival rate (DFS) was significantly worse in the DPP-4i intake group compared with non-intake group (5 year DFS 18.5% vs 5.4%, HR=2.0, p<0.05). The number of Zeb1-positive tumor cells significantly increased in DPP-4i intake group. (Median(M)=29.0 (0-189)/mm2 vs 9.0 (0-71)/mm2, p<0.01). The number of CD3 (+) TIL in DPP-4i intake group was Median(M)=277.4(min 121.6-max 523.2)/mm2 which was significantly lower than those in non-intake group (M= 319.6, min 493.0-max 823.6/mm2). CD8(+) TIL in DPP-4i intake was reduced more significantly than in non-intake group (M=187.6, min 67.8-max 347.4/mm2 vs M=336.8, min 200.2-max 588.4/mm2, p<0.05) with less CD8/CD3 ratio (61.2% vs 67.1%, p<0.05). On the other hand, the density of CD68(+)CD163(+) TAM was significantly higher(M=202.6, min 122.8-max 257.0/mm2 vs M=126.6, min 94.8-max 247.6/mm2, p<0.05) in DPP-4i intake group. Conclusion: DPP-4i increases the number of M2-type TAM while decreases the number of effector TIL and promote EMT of cancer cells in tumor microenvironment, which might lead to the poor outcome of the patients with CRC. Citation Format: Akira Saito, Hideyuki Ohzawa, Yuki Kaneko, Kohei Tamura, Yurie Futoh, Kazuya Takahashi, Yuki Kimura, Mineyuki Tojo, Rie Kawashima, Hideyo Miyato, Naohiro Sata, Joji Kitayama. Dipeptidyl peptidase-4 inhibitor impairs the outcomes of patients with type 2 diabetes mellitus after curative resection for colorectal 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 6379.
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Park, Sehhoon, Junghoon Shin, Chan-Young Ock, Chang Ho Ahn, Hyun Ae Jung, Se-Hoon Lee i Myung-Ju Ahn. "Abstract 7658: Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a prognostic biomarker for pembrolizumab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma". Cancer Research 84, nr 6_Supplement (22.03.2024): 7658. http://dx.doi.org/10.1158/1538-7445.am2024-7658.
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Abstract Background: Programmed cell death ligand 1 (PD-L1) expression alone has limited predictive value for pembrolizumab plus 5-fluorouracil and platinum (PFP) therapy in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). An artificial intelligence (AI)-powered spatial tumor-infiltrating lymphocyte (TIL) analyzer may provide independent prognostic information. Methods: This study included 63 patients with locally incurable HNSCC who received first-line PFP at Samsung Medical Center. Patients were classified into inflamed phenotype (IP) or non-inflamed phenotype (NIP) based on the 5% proportion threshold of inflamed 1 mm2-sized grids over total grids within hematoxylin and eosin-stained whole-slide images (WSIs) analyzed using Lunit SCOPE IO. We evaluated the prognostic value of inflamed status and densities of intratumoral TILs (iTILs), stromal TILs (sTILs), and tumor microenvironment TILs (tTILs). Results: Patients were predominantly male (78%). The median age at PFP initiation was 57 years. The most common primary tumor site was oral cavity (49.2%), followed by oropharynx (16%) and hypopharynx (10%). Of the 37 patients with available PD-L1 combined positive score (CPS), 2 (5%), 23 (62%), and 12 (32%) had CPS values of <1, 1-19, and ≥20, respectively. The overall response rate was 54%, with 67% in the CPS ≥20 subgroup and 48% in the CPS <20 subgroup. The median progression-free survival (PFS) was 7.2 months, with 10.8 months for patients with CPS ≥20 and 5.5 months for patients with CPS <20. The median overall survival (OS) was 18.6 months. Among 62 patients with available WSIs, 47 (74%) and 15 (26%) patients were categorized as having an IP and NIP, respectively. Oral cavity cancer was enriched with IP (57.4% of all IP cases vs 26.7% of all NIP cases), while all four paranasal sinus tumors had NIP. The overall response rate was 57% in the IP group and 44% in the NIP group. Patients with IP had significantly longer PFS and OS than patients with NIP, both in unadjusted (hazard ratio [HR] for PFS, 0.4; 95% confidence interval [CI], 0.21-0.78; P = 0.007; HR for OS, 0.43; 95% CI, 0.2-0.95; P = 0.036) and PD-L1 CPS-adjusted analyses (HR for PFS, 0.41; 95% CI, 0.21-0.79; P = 0.008; HR for OS, 0.4; 95% CI, 0.18-0.89; P = 0.025). High densities (≥25th percentile) of iTILs, sTILs, and tTILs were all significantly associated with prolonged PFS after CPS adjustment (P = 0.001, 0.001, and 0.012). High density of iTILs was also significantly associated with improved OS (P = 0.001 after CPS adjustment), while there was no significant association between OS and high density of sTILs or tTILs (0.077 and 0.085, respectively, after CPS adjustment). Conclusion: An AI-driven spatial TIL analyzer might serve as a simple and independent prognostic biomarker in HNSCC patients receiving pembrolizumab plus chemotherapy. Citation Format: Sehhoon Park, Junghoon Shin, Chan-Young Ock, Chang Ho Ahn, Hyun Ae Jung, Se-Hoon Lee, Myung-Ju Ahn. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a prognostic biomarker for pembrolizumab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7658.
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Shen, Lin, Yongqian Shu, Kuaile Zhao, Taroh Satoh, Zhendong Chen, Eric Van Cutsem, Guohua Yu i in. "Abstract CT077: Association of tumor mutational burden (TMB) and clinical outcomes with tislelizumab versus chemotherapy in esophageal cell carcinoma (ESCC) from RATIONALE-302". Cancer Research 83, nr 8_Supplement (14.04.2023): CT077. http://dx.doi.org/10.1158/1538-7445.am2023-ct077.
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Abstract Background: Programmed cell death protein 1 (PD-1) inhibitors are approved as second-line (2L) therapy for patients (pts) with ESCC. TMB is a predictive biomarker of response to immune checkpoint blockade in multiple cancers, but its role in ESCC is unclear. Here, we retrospectively investigated the association between TMB and clinical outcomes in the phase 3 RATIONALE-302 study of anti-PD-1 antibody tislelizumab (TIS) vs investigator-chosen chemotherapy (ICC) as 2L treatment for advanced unresectable/metastatic ESCC (NCT03430843). Methods: Genomic profiling was assessed on tumor tissues collected at baseline using BurningRock OncoScreen Plus 520 NGS panel to determine TMB status. Median progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Objective response rate (ORR) was calculated using the binomial exact method. Cox model was applied to assess the effect of TMB on survival outcomes. Hazard ratio (HR) and 95% confidence interval (CI) for OS and PFS in TMB subgroups were estimated. Results: Of 512 pts enrolled, 209 had evaluable tumor samples (TIS, n=105; ICC, n=104). Using the widely used cutoff of 10 mutations per megabase (mut/Mb), numerically higher ORR and survival benefit with TIS over ICC were observed in the high TMB (TMB-H) vs the low TMB (TMB-L) subgroup (Table). The predictive effect of TMB on survival outcomes was not significant (interaction p-value = 0.0537 for PFS, 0.5374 for OS); however, the effect became significant using the increased cutoff of 12 mut/Mb (TMB-H prevalence = 16.7%; interaction p-value = 0.0267 for PFS, 0.0175 for OS). Conclusions: TMB status may play a role in predicting clinical outcomes in pts with advanced ESCC treated with TIS versus ICC, especially when a higher TMB cutoff is chosen. These findings need further prospective validation. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Table. Clinical outcomes by TMB status (cutoff 10 mut/Mb) TMB status TMB-H TMB-L Treatment TIS ICC TIS ICC n (% in TMB BEP, N=209) 27 (12.9) 31 (14.8) 78 (37.3) 73 (34.9) ORR, % (95% CI) 33.3 (16.5, 54.0) 6.5 (0.8, 21.4) 16.7 (9.2, 26.8) 17.8 (9.8, 28.5) Median PFS, months (95% CI) 2.4 (1.4, 5.5) 2.3 (1.3, 2.9) 1.4 (1.3, 2.7) 2.7 (1.5, 3.3) PFS HR (95% CI) 0.52 (0.28, 0.97) 1.06 (0.73, 1.53) Interaction p-value 0.0537 Median OS, months (95% CI) 6.1 (4.2, 18.6) 4.7 (3.4, 7.0) 8.6 (4.6, 11.8) 7.0 (4.6, 8.6) OS HR (95% CI) 0.58 (0.32, 1.04) 0.72 (0.50, 1.03) Interaction p-value 0.5374 TMB-adjusted OS HR (95% CI) 0.68 (0.5, 0.92) BEP, biomarker evaluable population; CI, confidence interval; HR, hazard ratio; ICC, investigator chosen chemotherapy; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; TIS, tislelizumab; TMB-H, high tumor mutational burden; TMB-L, low tumor mutational burden; TMB-adjusted OS HR, overall HR adjusted for the impact of TMB on OS Citation Format: Lin Shen, Yongqian Shu, Kuaile Zhao, Taroh Satoh, Zhendong Chen, Eric Van Cutsem, Guohua Yu, Jun Wu, Chih-Hung Hsu, Sung Bae Kim, Wenting Du, Yang Shi, Ruiqi Huang, Qiao Li, Jingwen Shi, Yun Zhang, Kato Ken. Association of tumor mutational burden (TMB) and clinical outcomes with tislelizumab versus chemotherapy in esophageal cell carcinoma (ESCC) from RATIONALE-302 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT077.
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Gaspar, Cátia F., Natalie Y. Ngoi, Tin Tang, Jeffrey Ross, Dean Pavlick, Gregory Buchold, Shubham Pant, Milind Javle i Jordi Ahnert. "Abstract 963: Clinical impact of MTAP status in advanced cholangiocarcinoma: Genomic profile and response to treatment". Cancer Research 83, nr 7_Supplement (4.04.2023): 963. http://dx.doi.org/10.1158/1538-7445.am2023-963.
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Abstract Background: MTAP-loss is an emerging biomarker guiding druggable targets in cholangiocarcinoma and almost exclusively occurs in the setting of 9p21 loss, which has itself been associated with reduced IO responsiveness and poorer survival outcomes on a pan-cancer analysis. We sought to understand the clinical impact of MTAP status on treatment and survival outcomes, in a clinical cohort of molecularly characterized advanced cholangiocarcinoma patients. Methods: We analyzed advanced cholangiocarcinoma patients treated and evaluated at MD Anderson Cancer Center, tested for MTAP. Clinical information including genomic co-alterations, demographic information, treatment history and response to treatment were retrieved from retrospective medical record review. Comprehensive genomic profiling was performed with FDA-approved assays. Statistical analysis was performed with SPSS24 using Fisher's exact test, multivariate Cox regression and Kaplan-Meyer method for survival analysis. Results: 71 patients were identified (MTAP loss 31% (22/71); MTAP intact 69% (49/71)); 54,9% (39/71) were females. No significant difference in gender, age or ethnicity was seen between MTAP cohorts. We found that altered CDKN2A (p<0.01), CDKN2B (p<0.01), and IDH1 (p=0.048) were highly correlated with MTAP loss, while STK11 (p=0.095), a prognostic indicator of IO resistance, also showed a tendency to be a surrogate marker of MTAP loss status. Tumor mutational burden (TMB) was lower in MTAP loss group (2.18 vs. 4.88, p <0.01), but no difference was found in microsatellite instability (MSI) or PD-L1 status between groups. On multivariate analysis, patients harboring CDKN2A loss were noted to have worse OS compared to those without CDKN2A intact (18.6 vs 29.9 months, 95% CI, p=0.035). No statistically significant difference in OS was observed by MTAP status (25.9 vs. 29.2 months, 95% CI, p=0.168). Other genomic alterations with significant impact on OS were CCNE1 (p<0.01), FGF19 (p=0.04), and MYC (p=0.043). Treatment with chemotherapy regimens containing Gemcitabine in the first line setting of metastatic disease showed higher disease control rate in the MTAP intact cohort (91.4%) vs. MTAP loss cohort (38.5%) (p<0.01), but no statistically significant difference in response (PR/CR) (p=0.421). Few patients (14/71) received IO in this cohort; no significant difference in IO response was observed by MTAP status (p=0.152). Conclusions: MTAP loss cholangiocarcinoma has a distinct molecular profile compared with MTAP intact including key differences in co-altered tumor suppressor genes and TMB. To our knowledge, this is the first real-world data describing the clinical and genomic differences in advanced cholangiocarcinoma by MTAP status. Further prospective data are required to validate these findings. Citation Format: Cátia F. Gaspar, Natalie Y. Ngoi, Tin Tang, Jeffrey Ross, Dean Pavlick, Gregory Buchold, Shubham Pant, Milind Javle, Jordi Ahnert. Clinical impact of MTAP status in advanced cholangiocarcinoma: Genomic profile and response to treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 963.
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Grasso, Luigi, J. Bradford Kline i Nicholas C. Nicolaides. "Abstract 1876: NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of potent payload by counteracting MUC16/CA125 effects". Cancer Research 83, nr 7_Supplement (4.04.2023): 1876. http://dx.doi.org/10.1158/1538-7445.am2023-1876.
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Abstract Subsets of tumor-produced proteins, referred to as Humoral Immuno-Oncology (HIO) factors, can bind to IgG1 antibodies and suppress their immune-effector activities. Antibody-drug conjugates (ADCs) targeting tumor cell surface antigens can internalize and kill target cells upon liberation of their cytotoxic payload. Binding of the antibody component of an ADC by a HIO factor may potentially hamper the efficacy of a bound ADC. To assess any suppression of ADC’s activity by HIO factors, we evaluated the efficacy of a HIO-refractory ADC, NAV-001, and a HIO-bound ADC, SS1, both targeting mesothelin. The HIO factor MUC16/CA125 protein, which binds to SS1 ADC, was shown to have a negative effect on its internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of tumor cells regardless of MUC16/CA125 expression in vitro (EC50 ~20 pM) as well as in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor as a payload, demonstrated good stability in vitro and in vivo as well as robust bystander activity against tumor and stromal cells not expressing the target antigen mesothelin, while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenograft models from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed for NAV-001 and warrants NAV-001-PNU’s advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers. Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. NAV-001, a high-efficacy antibody-drug conjugate targeting mesothelin with improved delivery of potent payload by counteracting MUC16/CA125 effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1876.
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Tahk, Siret, Kai Virumae, Korneelia Anton, Paule Hermet, Robin Pau, Mario Plaas, Maiken Abel i in. "Abstract 1876: Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth". Cancer Research 84, nr 6_Supplement (22.03.2024): 1876. http://dx.doi.org/10.1158/1538-7445.am2024-1876.
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Abstract Background: Upregulated glucose metabolism is one of the strategies cancer cells use to fuel their abnormal cell growth and division. Targeting the cancer-specific glucose transporter GLUT-1 is a promising approach to restrict glucose uptake and challenge the metabolic needs of tumor cells. Antibodies, as opposed to small molecule inhibitors, are an attractive modality to therapeutically target complex muti-pass membrane transporters. Here we report the development of antibodies that very specifically block the function of only GLUT-1. Methods: Monoclonal antibodies against GLUT-1 were generated using virus-like particles. For immunization, chickens were used as they are evolutionarily distant from mammals and can produce antibodies with prolonged CDR3-s in VH, which could facilitate their binding to the limited extracellular region of GLUT-1. Antibody discovery was performed with HybriFree B cell cloning technology followed by functional screens with 2-deoxyglucose uptake interference or cell proliferation measurements. Results: The discovered antibodies specifically bind to GLUT-1 with low nanomolar EC50 values and do not target other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and rewires the metabolism of GLUT-1-dependent cancer cells to rely on oxidative phosphorylation. This results in a significantly synergistic cancer proliferation inhibition with ICO-33 and OXPHOS inhibitor combinations in doses that do not inhibit proliferation as single agents. ICO-33 and OXPHOS inhibitor treatment is well-tolerated and demonstrates a drastic tumor growth inhibition in in vivo colorectal and pancreatic cancer models. Conclusions: We describe the discovery of highly specific monoclonal antibodies targeting GLUT-1. We further demonstrate that the restriction of the much-needed glucose uptake by ICO-33 makes cancer cells highly susceptible to OXPHOS inhibitor co-therapy both in vitro and in vivo, validating the antibody as a promising candidate for clinical development. Citation Format: Siret Tahk, Kai Virumae, Korneelia Anton, Paule Hermet, Robin Pau, Mario Plaas, Maiken Abel, Denis Belitškin, Luciano Galdieri, Steven Garner, Jillian Krings, Kaleb Collver, Emily Schultz, Kaitlyne Powers, Alastair King, Francisca Neethling, Anu Planken, Mart Ustav, Joan Terya, Andres Mannik, Mart Ustav. Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1876.
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Xu, Kailun, Xiaoyang Yin, Tiannan Guo, Shu Zheng i Yingkuan Shao. "Abstract 7093: Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics". Cancer Research 84, nr 6_Supplement (22.03.2024): 7093. http://dx.doi.org/10.1158/1538-7445.am2024-7093.
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Abstract The use of adjuvant therapy in stage II-III colon cancer (CC) has been controversial for decades. No markers or models now is satisfactory enough to be adopted widely by the medical community. Here, we analyzed the proteomics of paraffin-embedded tissue (FFPE) biopsy samples from 230 CC patients (stages II-III) with up to 10 years of survival by using pressure cycling technology (PCT) and data-independent acquisition (DIA) mass spectrometry. Using machine learning, we established a novel and practical protein-based clinical classification system for CC prognosis which was further verified in an independent validation cohort. Using the nine protein-based clinical model, we improved the area under the curve (AUC) value to 0.926 in the training cohort and 0.872 in the validation cohort. Our promising model will be a potential approach to prognostication to aid in rational follow-up schedule-making and risk-adaptive individualized therapies. Citation Format: Kailun Xu, Xiaoyang Yin, Tiannan Guo, Shu Zheng, Yingkuan Shao. Prediction of overall survival in stage II and III colon cancer through machine learning of rapidly-acquired proteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7093.
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Jeon, Junhyeok, Eujin Hong i Hyun Uk Kim. "Abstract 4923: A systematic framework for predicting adverse drug reaction signals using medical data". Cancer Research 84, nr 6_Supplement (22.03.2024): 4923. http://dx.doi.org/10.1158/1538-7445.am2024-4923.
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Abstract Prescribing a combination of medications is a common strategy to enhance the effectiveness of disease treatment. While this approach aims to improve therapeutic outcomes, it may lead to unintended adverse drug reactions (ADRs) due to interactions between prescribed drugs and individual factors. Recognizing the importance of ADRs, various machine learning models have been developed. However, these models face limitations, particularly in predicting reactions induced by three or more drugs and in accounting for individual patient factors, such as age and medical history. To address these limitations, we propose a systematic framework that leverages medical data for predicting ADR signals. In the framework, the MIMIC-IV database was systematically preprocessed, and a series of machine learning models were developed that predict the ADR signals. The model predictions were validated using the eICU collaborative research database. The machine learning models process multiple inputs, including information on administered drugs, age, gender, ethnicity, and underlying medical conditions to predict ADR signals. The ADR signals are determined by classifying abnormalities in 20 specific laboratory test values, such as hematocrit, creatinine, and hemoglobin. The machine learning models developed in this study hold promise as a valuable tool for assessing potential risks, such as ADRs, associated with the concurrent use of multiple drugs. Citation Format: Junhyeok Jeon, Eujin Hong, Hyun Uk Kim. A systematic framework for predicting adverse drug reaction signals using medical data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4923.
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Cheung, Christian S., Nathan W. Sweeney, Zena M. Tiu, Cynthia Chmielewski i Jennifer M. Ahlstrom. "Abstract 6287: Comparison of multiple myeloma provider for Black Americans and Caucasian Americans". Cancer Research 82, nr 12_Supplement (15.06.2022): 6287. http://dx.doi.org/10.1158/1538-7445.am2022-6287.
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Abstract Background: Although Black Americans have 2-3 times multiple myeloma (MM) incidence and mortality as compared to Whites, increasingly research is demonstrating that many may have genetic characteristics that have better survival outcomes. Yet delayed diagnoses and inappropriate first lines of therapy often wipe out whatever “advantages” they may have had, keeping mortality statistics higher than would be expected (PMID: 25469920). For underserved populations, a number of commonly accepted disparities exist in myeloma, and more broadly, cancer care. Patients who receive treatment by a high-volume provider (myeloma specialist) is a factor that can help patients with MM to have a longer life expectancy (PMID: 31487686). Therefore, we analyzed whether there is a disparity between race and receiving care from a myeloma specialist which may contribute to the differences in survival that is being seen. Methods: Validated real-world (RW) MM patient data was collected through HealthTree Cure Hub for Multiple Myeloma (healthtree.org). We examined the patient’s race which was either Caucasian American or Black American and whether or not they were being treated by a myeloma specialist. The association between race and specialist was examined by a chi-squared (X2) test. Results: In this retrospective analysis of 2,871 MM patients, we compared Caucasian Americans (n= 2716) and Black Americans (n=155). Our analysis revealed a significant association between the two races and whether or not they had a myeloma specialist, X2(1, N = 2,871) = 5.85, p = 0.015. Black Americans were less likely to be treated by a myeloma specialist. Conclusion: The findings of this RW analysis identify a glaring disparity in Black American MM patients and receiving care from a myeloma specialist. Addressing the underlying cause of the findings could extinguish other MM-related issues, such as delays in getting a correct diagnosis, lack of access to myeloma specialists, and many other non-medical issues leading to less-than-optimal outcomes from the majority of these Black American patients. Citation Format: Christian S. Cheung, Nathan W. Sweeney, Zena M. Tiu, Cynthia Chmielewski, Jennifer M. Ahlstrom. Comparison of multiple myeloma provider for Black Americans and Caucasian Americans [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 6287.
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Gurjao, Carino, Edmond Chan, Michael J. Lee, Sho Hangai, Raul Rabadan, Tal Korem, Hanina Hibshoosh i Benjamin Izar. "Abstract 994: Single analyte profiling of the mutational, immune and microbiome landscape in african american colon cancer patients". Cancer Research 84, nr 6_Supplement (22.03.2024): 994. http://dx.doi.org/10.1158/1538-7445.am2024-994.
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Abstract Colorectal cancer (CRC) disproportionately affects African American (AA) patients who experience a higher incidence and mortality than any other demographic groups in the United States. Yet molecular profiling in this population is scarce. Here, we performed whole-exome sequencing (WES) of 342 immediately snap-frozen tissues comprising AA CRC and matched, distant normal colon and identified distinct genomic drivers, DNA signatures, and, surprisingly, mosaic pathogenic mutations that are not present in the patient-matched CRC. We inferred T cell infiltration and tissue-resident microbiome (TR-M) directly from WES, enabling integrative analyses. Compared to normal colon, T cell infiltration is strongly decreased in tumours with microsatellite stability (MSS), while microsatellite unstable (MSI) and Polymerase Epsilon (POLE) mutant tumours had similar levels, suggesting immune evasion in MSS rather than increased T cell infiltration in MSI/POLE-mutants. Analyses of matched normal and tumour tissues revealed the evolving TR-M at unprecedented granularity and identified distinct niches of interactions with genomic and tumour-microenvironmental features. Together, this study represents the largest comprehensive genomic analysis of CRC in AA and provides a framework for performing a multi-layered analysis from a single analyte, thus, affording a cost-effective approach to expedite medical discoveries in underrepresented ancestries. Citation Format: Carino Gurjao, Edmond Chan, Michael J. Lee, Sho Hangai, Raul Rabadan, Tal Korem, Hanina Hibshoosh, Benjamin Izar. Single analyte profiling of the mutational, immune and microbiome landscape in african american colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 994.
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Jiao, Meng, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton i in. "Abstract LB280: Enhancing glioblastoma radiotherapy by COMT inhibition". Cancer Research 84, nr 7_Supplement (5.04.2024): LB280. http://dx.doi.org/10.1158/1538-7445.am2024-lb280.
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Abstract There is an urgent unmet medical need to discover novel therapeutics to enhance the efficacy of glioma radiotherapy. Here we assessed the roles of catechol - o - methyltransferase COMT, a key enzyme in dopamine metabolism and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in glioma versus normal brain tissues. Inhibition of COMT by genetic knockout or FDA - approved COMT inhibitors significantly sensitized glioma cells to radiotherapy in vitro and murine glioma in vivo. Mechanistically, COMT inhibition in glioblastoma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral dsRNA sensing pathway and type I IFN response. Elevated type I IFNs stimulated microglial cells′ phagocytic capacity, enhancing radiotherapy efficacy. Because of the long - established safety record of the COMT inhibitors, our findings provide a solid rationale to evaluate them in combination with radiotherapy in glioma patients. Citation Format: Meng Jiao, Christopher J. Pirozzi, Chen Yu, Xuhui Bao, Mengjie Hu, Dong Pan, Sejiro Littleton, Nathan Reynolds, Daniel R. Saban, Fang Li, Chuan-yuan Li. Enhancing glioblastoma radiotherapy by COMT inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB280.
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Collin, Lindsay Jane, Courtney Johnson, Maxwell Akonde, Mary Kan, Elisa V. Bandera, Lauren Peres, Anthony Alberg, Theresa Hastert i Joellen Schildkraut. "Abstract 4837: Perceived discrimination, medical mistrust, and their associations with ovarian cancer mortality among women in the African American Cancer Epidemiology Study". Cancer Research 84, nr 6_Supplement (22.03.2024): 4837. http://dx.doi.org/10.1158/1538-7445.am2024-4837.
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Abstract Background: There are pronounced racial disparities in ovarian cancer mortality wherein Black women are on average 30% more likely to succumb to their disease than White women. Factors that contribute to these disparities are complex and multifactorial. Racial discrimination is hypothesized to affect cancer health disparities through three distinct pathways including the impact on socioeconomic inequities, chronic stress, and restricted access to goods and services. In this study, we examined the role of perceived discrimination and medical mistrust on all-cause mortality among ovarian cancer patients. Methods: Using data from the African American Cancer Epidemiology Study (AACES), we included 592 ovarian cancer patients who self-identified as Black or African American and completed a telephone interview. Perceived discrimination was measured with a modified version of the 5-question Williams Everyday Discrimination scale. Medical mistrust was measured with the Trust in Physician scale (ranged 0-48 based on a combination of 12 questions). We used Cox proportional hazard models to compute hazard ratios (HR) and 95% confidence intervals (CIs) associating perceived discrimination and medical mistrust with all-cause mortality, adjusting for age, stage, and histotype. Results: Nearly two-thirds of the cohort passed away by the end of follow-up (mean follow-up 5.5 years, ranging 0.5-12 years). We observed that 231 participants patients (39%) reported experiencing discrimination in at least one of the domains assessed. Reporting any experience of discrimination was associated with lower all-cause mortality (HR=0.78, 95% CI: 0.62, 0.97). In multivariable adjusted models, higher trust in physicians (above vs. below the median of 35) was associated with a decreased risk of mortality (HR=0.87, 95% CI: 0.70, 1.08). Conclusion: In our preliminary results, we observed an association between any experience of discrimination and better survival, and that a higher trust in physicians was associated with better survival. Further work on this project will try to understand the paradoxical association with perceived discrimination, and evaluate the associations of discrimination and medical mistrust with ovarian cancer treatment, leading to more insight into drivers of racial disparities in ovarian cancer mortality. Citation Format: Lindsay Jane Collin, Courtney Johnson, Maxwell Akonde, Mary Kan, Elisa V. Bandera, Lauren Peres, Anthony Alberg, Theresa Hastert, Joellen Schildkraut. Perceived discrimination, medical mistrust, and their associations with ovarian cancer mortality among women in the African American Cancer Epidemiology Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4837.
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Mueller, Joerg P., Nils O'Brien, Franz Osl, Frank Herting, Christian Klein, Pablo Umana, Sara Colombetti, Thomas Poeschinger i Andreas Beilhack. "Abstract 1876: ROCKETS Science: A novel processing toolbox for light sheet microscopy reveals unknown binding sites for EpCAM-targeted antibodies". Cancer Research 82, nr 12_Supplement (15.06.2022): 1876. http://dx.doi.org/10.1158/1538-7445.am2022-1876.
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Abstract Summary: We present a novel light sheet fluorescence microscopy (LSFM)-based imaging platform and corresponding set of procedures for greatly improved preclinical investigation of the biodistribution of novel drug candidates by the example of an EpCAM-targeting antibody. Methods: An anti-EpCAM antibody (G.8.8R) was applied intravenously to mice. Whole mice or individual organs were optically cleared following novel protocols, which we termed Rapid Optical Clearing Kit for Enhanced Tissue Scanning (ROCKETS). The procedures enabled processing of mouse organs and entire bodies for LSFM. For the GI tract, we developed 3D-Swiss rolls, a method that enables fixation, clearing and imaging of intestines in a compact form as a whole. The new procedures allowed us to investigate the biodistribution of G.8.8R in the entire mouse body and highly detailed in individual organs. Results: The ROCKETS concept achieved full transparency of any mouse organ, the entire GI tract and whole mouse bodies. All positive organs were easily identified in scans of whole mice, thereby providing excellent guidance for scanning of positive individual organs at higher magnifications. We detected G8.8R bound to all normal cuboidal and columnar epithelia, as well as in lymphoid organs and were able to reproducibly score binding levels. All reported EpCAM+ tissues in mice were accessed by G8.8R after intravenous application and binding was restricted to basolateral membranes of epithelia, as expected from published expression analyses. Moreover, we detected G8.8R in tissues that were reported EpCAM- or were not investigated, e.g. gustatory papillae of the tongue, choroid plexi in the brain or lingual mucous salivary glands. 3D-Swiss rolls of the GI tract revealed a highly heterogeneous binding pattern in the stomach, while the pattern along the small intestine was overall homogeneous. All binding was restricted to basolateral membranes of epithelial cells. We detected a general gradient of signals, decreasing from the bottom of the crypts to differentiated cells in all tissues, corresponding to described EpCAM downregulation with progressing differentiation. Furthermore, we first describe significantly increased signals at the common bile duct, major and minor duodenal papillae, as well as the mucosa in proximity of Peyer's patches (PP). Conclusions: The developed ROCKETS toolbox allowed for simple preparation of mouse organs and bodies for high-quality LSFM imaging. Our investigations of the highly heterogeneous biodistribution of G8.8R revealed previously unknown EpCAM binding locations, which may have far-reaching implications for EpCAM-targeting therapeutics in general, many of which failed in clinical studies due to dose limiting toxicities. In the future, the developed LSFM-imaging platform may contribute valuable data to preclinical drug development studies of any targeted therapeutic. Citation Format: Joerg P. Mueller, Nils O'Brien, Franz Osl, Frank Herting, Christian Klein, Pablo Umana, Sara Colombetti, Thomas Poeschinger, Andreas Beilhack. ROCKETS Science: A novel processing toolbox for light sheet microscopy reveals unknown binding sites for EpCAM-targeted 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 1876.
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Jeon, Junhyeok, Eujin Hong i Hyun Uk Kim. "Abstract 3170: Predicting the signals of adverse drug reactions on the basis of medical data". Cancer Research 83, nr 7_Supplement (4.04.2023): 3170. http://dx.doi.org/10.1158/1538-7445.am2023-3170.
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Abstract Multiple drugs are often prescribed for the better treatment of a disease. While the use of multiple drugs is to improve the overall therapeutic efficacy, it can also lead to unintended adverse drug reactions (ADRs) from drug-drug interactions (DDIs). More than 30% of ADRs have been reported to be caused by DDIs. Because of the importance of DDIs and ADRs, many computational models have been developed to predict DDIs and/or ADRs. However, these computational models mostly make predictions on the basis of molecular features of drugs without considering clinical factors, which consequently does not allow predictions in a person-specific manner. To address this problem, we present a machine learning model that predicts the signals of ADRs potentially caused by DDIs on the basis of medical data. Medical data used for model development come from MIMIC-IV, and include age, ethnicity, gender, patients’ disease information (i.e., ICD-10) and information on drugs administered (e.g., molecular structure and dose). The medical data were subjected to extensive preprocessing based on a domain knowledge, and multiple machine learning methods were examined to predict the ADR signals using the preprocessed dataset. ADR signals are captured by classifying whether each of the selected laboratory measurements (e.g., hematocrit, creatinine, and hemoglobin) is normal. The best-performing model showed the average AUROC of more than 0.8. The machine learning model developed in this study can be useful for examining potential harms when considering multiple drugs, including anticancer drugs. Citation Format: Junhyeok Jeon, Eujin Hong, Hyun Uk Kim. Predicting the signals of adverse drug reactions on the basis of medical data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3170.
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Adewunmi, Mary Adetutu. "Abstract 6391: Scalable colorectal cancer (CRC) diagnosis model with arterial and unenhanced phases of KRAS mutational status using Apache Spark". Cancer Research 82, nr 12_Supplement (15.06.2022): 6391. http://dx.doi.org/10.1158/1538-7445.am2022-6391.
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Abstract The exponential increase in Medical data and Computer-aided diagnostic tools has made it easier for Machine Learning (ML) Researchers to extract valuable insights from medical images resulting in better patient outcomes during Medical Summarization. According to current statistics, 8.8 million people died every year due to cancer death. It is therefore imperative to use these available image datasets for better diagnosis, increased patient outcomes and recovery from deadly diseases. As a result, this study proposes a Colorectal Cancer classification model for detecting KRAS mutation status of Patients through their Radiomic images using the transfer learning of a deep learning pipeline on Apache Spark. The datasets will be curated from National Cancer Institute (NCI), features extraction or classification of Computed tomography(CT) images into CT- based handcrafted radiomic signatures with a Convolutional Neural Network(CNN) using the Apache Spark framework, the system uploads the segmented scanning images to the High Distributed File System (HDFS), Confidence Interval(CI), Area Under Curve(AUC), Precision and Recall for Validation cohort, Docker for app deployment and containerization of the model developed for reproducibility, transfer learning and model reuse. The result would be a real-time model using Deep learning pipelines with Apache Spark and Keras Tensor flow for KRAS Mutation detection using Colorectal Cancer images. In conclusion, this research project would produce a scalable and reproducible model for the faster diagnosis of Colorectal Cancer through the KRAS mutation status of CRC Patients. Citation Format: Mary Adetutu Adewunmi. Scalable colorectal cancer (CRC) diagnosis model with arterial and unenhanced phases of KRAS mutational status using Apache Spark [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 6391.
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Chido-Amajuoyi, Onyema, Ikenna Nnamani i Owhofasa Agbedia. "Abstract 751: Disparities in physician office visit wait time among US cancer survivors". Cancer Research 83, nr 7_Supplement (4.04.2023): 751. http://dx.doi.org/10.1158/1538-7445.am2023-751.
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Abstract Background: Disparities are well-documented in the time spent seeking medical care in the US. Studies have found that minority populations are likely to have longer wait times securing healthcare access and higher total time spent at clinic visits. However, this relationship has not been previously examined among the cancer survivor population, which constitutes about 17 million people in the US. Methods: Study data were derived from the 2018 National Health Interview Survey, a nationally representative survey of US adults. Study sample was restricted to cancer survivors (n=2,940; N=23,310,174). The primary outcome of this study was reports of prolonged wait times during doctor office visits. Weighted multivariable logistic regression were used to estimate adjusted associations between prolonged wait times during doctor office visits and sociodemographic and behavioral characteristics of cancer survivors. All analyses were conducted using STATA version 14.2. Results: Respondents who identified as Black/African American were almost 3 times more likely than their White counterparts to report prolonged wait times during doctor office visits (aOR 2.65, 95% CI; 1.296, 5.419). Similarly, respondents who identified as Hispanic were almost 3 times more likely than non-Hispanic respondents to report prolonged wait times during doctor office visits (aOR 2.604, 95% CI; 1.347, 5.035). Respondents in the $50,000 - $74,999 income bracket were less likely to report prolonged wait times during doctor office visits than respondents who earned less than $35,000 (aOR: 0.50, 95% CI, 0.276, 0.916). Conclusion: Black/African American and Hispanic cancer survivors had increased odds of reporting prolonged wait times during doctor office visits. Disparities in cancer health and survivorship are well documented among racial minorities. Addressing disparities in healthcare experiences and access will be crucial in dispelling existing cancer health disparities. Citation Format: Onyema Chido-Amajuoyi, Ikenna Nnamani, Owhofasa Agbedia. Disparities in physician office visit wait time among US cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 751.
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Huang, Ying, Heather Basehore, Emily S. Boja i Jaime M. Guidry Auvil. "Abstract 1303: Harness the power of data to improve cancer care - Understanding the complex landscape of health policies and regulations". Cancer Research 84, nr 6_Supplement (22.03.2024): 1303. http://dx.doi.org/10.1158/1538-7445.am2024-1303.
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Abstract In the era of big data and artificial intelligence, biomedical research and healthcare have been presented with unprecedented opportunities for improving the understanding of cancer biology. In addition, the Open Science Initiative aims to shift the current paradigm of research practice towards broad sharing and public access to research findings as the norm. Big data in oncology usually includes a combination of genomic sequencing, proteomics, medical imaging, electronic health records, payor records, and other data sources from pharmaceutical research, wearables, and medical devices. While combining, linking, and analyzing data from different sources across research and healthcare enterprises is key to realizing the promise of big data and a health learning system, it poses tremendous challenges for researchers and implementers to understand the nuances of relevant policies, laws, and regulations while striving for broad, equitable, timely and responsible data sharing, as well as tackling issues in data quality, harmonization, interoperability, and security. Herein, we aim to shine a light on the ever-evolving landscape of data privacy regulations, laws, and policies that govern different touch points of a patient's journey where data are collected for research and healthcare purposes throughout the lifecycle that would impact data-sharing outcomes. We hope the illumination of a complex landscape of data governance framework to consider for many data sources will facilitate broad community engagement including data scientists and technologists, patients and advocacy groups, and policymakers to maximize open data and science while protecting patient privacy and confidentiality. Citation Format: Ying Huang, Heather Basehore, Emily S. Boja, Jaime M. Guidry Auvil. Harness the power of data to improve cancer care - Understanding the complex landscape of health policies and regulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1303.
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Villani, Tom, Jigar Patel, Kim Collins, Kate Lillard Tunstall i Bradley Krisanits. "Abstract 3864: Cytometric analysis of immune cell populations in clinical tumor biopsy tissue microarrays for immuno-oncology". Cancer Research 82, nr 12_Supplement (15.06.2022): 3864. http://dx.doi.org/10.1158/1538-7445.am2022-3864.
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Abstract Over the past decade, a new focus on the interactions between the immune system and the development and progression of cancer has led to a wide array of research into medical treatments which leverage activation or modulation of the immune system to aid in treatment. Research in the field of immuno-oncology and elucidation of the biological mechanisms by which cancer cells suppress immunological function has led to new biological treatments for cancer, such as pembrolizumab, which have shown great clinical success since their advent. Population-level analysis of immune cell populations is critical for understanding the immune-component of disease progression, and flow cytometry is a commonly utilized technique for this purpose. However, flow cytometry requires dissolution of tissue specimens, and is incompatible with formalin-fixed paraffin-embedded (FFPE) samples, the gold standard in tissue archives. In order to allow for cytometric analysis of FFPE tissues, we have developed a digital pathology technique for the quantitative assessment of immune-cell populations within tissue microarrays prepared from archived FFPE clinical tissue specimens from patient biopsies. The technique involves a combination of HALO® image analysis using the Highplex FL, Spatial Analysis, and TMA modules, and custom scripting to develop imaging cytometry scatterplots. Bioinformatics techniques were utilized to assess features correlated with tumor progression from the quantitative data extracted from the tissue microarrays. Citation Format: Tom Villani, Jigar Patel, Kim Collins, Kate Lillard Tunstall, Bradley Krisanits. Cytometric analysis of immune cell populations in clinical tumor biopsy tissue microarrays for immuno-oncology [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 3864.
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Awoke, Wondimu Ashagre. "Abstract 2246: Prevalence of mycobacterium tuberculosis among PAP smear samples of cervical cancer suspects". Cancer Research 83, nr 7_Supplement (4.04.2023): 2246. http://dx.doi.org/10.1158/1538-7445.am2023-2246.
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Abstract Introduction: Cervical cancer is one of the most common cancers in women around the world. The Pap smear test is the most common method of detecting abnormal cells that may develop into cancer. In addition, we want to know how common mycobacterium tuberculosis is among those who provide Pap smear samples. Objectives: The purpose of this study is to examine the knowledge, attitudes, and practices of working women in Addis Abeba, Ethiopia, regarding cervical cancer and Pap smear tests, as well as the associations between knowledge, attitudes, and practices and socio-demographic factors. In addition, we will investigate the prevalence of mycobacterium tuberculosis from smears among those who provide Pap smear samples. Methods: This will be a cross-sectional questionnaire-based study of 100 Ethiopian females' attending at Arsho medical laboratories from September to December 2022, knowledge, attitudes, and practices, as well as the prevalence of tuberculosis. All women between the ages of 20 and 65 who wanted to be diagnosed with cervical cancer were eligible. Expected outcome: To teach and recall common cervical cancer symptoms such as menstrual bleeding, the appropriate age for Pap smear tests, and the interval between tests. Examine their use of hormonal contraception and their attitude toward Pap smear testing over the last five years. It will also be useful to know the prevalence of cervical tuberculosis. Citation Format: Wondimu Ashagre Awoke. Prevalence of mycobacterium tuberculosis among PAP smear samples of cervical cancer suspects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2246.
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Mohan, Dipika R., Kleiton S. Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, Donald W. Little, Tobias Else i in. "Abstract 1501: Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer". Cancer Research 83, nr 7_Supplement (4.04.2023): 1501. http://dx.doi.org/10.1158/1538-7445.am2023-1501.
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Abstract Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical therapies. CIMP-high is an aggressive ACC molecular subtype defined by global CpG island hypermethylation with paradoxical activation of adrenal differentiation (driven by master transcription factor SF1) and stemness (driven by β-catenin). We show DNA hypermethylation redistributes histone methyltransferase EZH2 and its mark, H3K27me3. EZH2 inhibition remains lethal to CIMP-high ACC cells, erasing transcriptional programs without altering DNA methylation. We reconcile this phenomenon by discovery of two nuclear complexes, SF1/β-catenin and EZH2/β-catenin, present in physiology and persistent through advanced ACC. We find SF1/β-catenin is a chromatin-bound complex that controls the ACC super-enhancer landscape, while EZH2/β-catenin is restricted to off-chromatin pools. EZH2 inhibition purges SF1/β-catenin from chromatin, sparing EZH2/β-catenin, inducing dedifferentiation and restraining ACC growth in vitro and in vivo. Our studies illustrate how cell-of-origin programs dictate cancer evolution, exposing differentiation as an therapeutic vulnerability. Citation Format: Dipika R. Mohan, Kleiton S. Borges, Isabella Finco, Christopher R. LaPensee, Juilee Rege, Donald W. Little, Tobias Else, Madson Q. Almeida, Derek Dang, James Haggerty-Skeans, Ana Claudia Latronico, Berenice B. Mendonca, Richard J. Auchus, William E. Rainey, Suely K. Marie, Thomas J. Giordano, Sriram Venneti, Maria Candida B. Fragoso, David T. Breault, Antonio M. Lerario, Gary D. Hammer. Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1501.
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Gaddam, Shiva Jashwanth, Udhayvir Singh Grewal, Zara Hassan i Poornima Ramadas. "Abstract 6497: Availability of healthcare providers and its association with survival outcomes in non-Hodgkin lymphoma in the United States". Cancer Research 83, nr 7_Supplement (4.04.2023): 6497. http://dx.doi.org/10.1158/1538-7445.am2023-6497.
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Abstract Background: Survival outcome in Non-Hodgkin lymphoma (NHL) is significantly better in earlier stages, compared to advanced stages. Early identification of signs and symptoms, and prompt specialist availability and referral, are crucial for diagnosis and treatment at earlier stages. Mounting physician shortages are a growing concern, and we sought to analyze their effect on NHL mortality rates. Methods: We extracted data on the age-adjusted mortality rate (AAMR) and crude incidence rate (CIR) of NHL for all U.S. states and the District of Columbia from the Center for Disease Control (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database (2017-2019). Nevada was excluded due to missing information. Data on the state-wise number of primary care physicians (PCPs) was obtained from the Association of American Medical Colleges (AAMC) state physician workforce data report (2020), and of Hematology/Oncology specialists (HOs) was gathered from the National Provider Identifier (NPI) registry (2020). The number of PCPs and HOs per each NHL incidence (PCP/CIR, HO/CIR respectively) was then calculated. Correlations were analyzed using Pearson’s coefficient. Statistical analysis was performed using VassarStats. Results: Median AAMR for NHL in the US was 5.15 (IQR 4.35, 5.95) per 100, 000 population. The median number of PCP and HO per each case of NHL incidence was 4.32 (IQR 3.43, 5.21), and 0.28 (IQR 0.1, 0.37) respectively. States with fewer PCPs per each NHL incidence had higher AAMR (r=-0.37, p=0.007). States with a lower number of HOs per each NHL incidence had higher AAMR (r=-0.41, p=0.003) Conclusions: Based on the analysis, the availability of a lower number of PCPs and HOs per each NHL incidence is associated with increased AAMR of the disease. This data may strengthen the need for intensification of focus on decreasing the soaring physician shortages in the states, in order to help decrease the overall mortality associated with NHL. Citation Format: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Zara Hassan, Poornima Ramadas. Availability of healthcare providers and its association with survival outcomes in non-Hodgkin lymphoma in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6497.
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Lee, Hyunjung, Dongjun Lee, Ding Quan Ng, Daniel Wiese, Ahmedin Jemal i Farhad Islami. "Abstract 797: Area deprivation, rurality, healthcare utilization, quality of life, and health status among cancer patients". Cancer Research 84, nr 6_Supplement (22.03.2024): 797. http://dx.doi.org/10.1158/1538-7445.am2024-797.
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Abstract Background: Living in deprived or rural neighborhoods can negatively influence individual health through various mechanisms, including limited access to care due to scarce resources, medical facilities, or health professionals. Prior ecological studies have shown an association between living in rural or disadvantaged areas and higher cancer morbidity or mortality, but research on the association between neighborhood of residence and cancer patients’ healthcare utilization, health status, or quality of life has been limited. Method: We used survey and electronic health records data on cancer patients aged ≥18 years (N=16,606) from All of US Controlled Tier Dataset v7 (summer 2017-July 1, 2022). Area deprivation index (ADI) was based on six items, including 3-digit zip code-level median household income, proportions of high school graduation, vacant housing, recipients of public assistance income, and individual without health insurance or with incomes below the poverty level. Rural-urban status was defined at the 3-digit zip code-level as urban (100% urban), mostly urban (≥50%-<100% urban), and rural (>50% rural). Logistic regression models were used to estimate the association between ADI or rurality and health care utilization (general doctor, specialist, mental health, or nurse practitioner/physical assistant [NP/PA] visits) or health outcome (fair/poor physical and mental health status, quality of life), controlling for various covariates. Results: Cancer patients living in the most deprived areas (ADI 5th quintile) were less likely to have general doctor visits (OR=0.73; 95% CI=0.54-0.85), NA/PA visits (OR=0.87; 95% CI=0.77-0.99), or mental health professional visits (OR=0.85; 95% CI=0.74-0.98), and more likely to have fair or poor quality of life (OR=1.31; 95% CI=1.06-1.62), compared to those living in the least deprived areas (ADI 1st quintile), controlling for all covariates. Similarly, rural cancer patients were less likely to have general doctor visits (OR=0.58; 95% CI=0.42-0.79) or mental health professional visits (OR=0.53; 95% CI=0.41-0.67), and more likely to have fair/poor physical health (OR=1.27; 95% CI=1.03-1.57), compared with urban cancer patients. However, rural cancer patients were more likely to have NA/PA visits (OR=1.29; 95% CI=1.04-1.58) and less likely to have fair/poor mental health (OR=0.66; 95% CI=0.48-0.92). Cancer patients in mostly urban areas showed similar patterns to those in rural areas but the magnitudes of associations were smaller. Conclusions: In this study, cancer patients living in deprived or rural areas were less likely to have general doctor or mental health professional visits and more likely to have poor physical health compared to patients in the least deprived or urban area. Community-level interventions in deprived or rural areas are required to mitigate disparities in healthcare and health among cancer patients. Citation Format: Hyunjung Lee, Dongjun Lee, Ding Quan Ng, Daniel Wiese, Ahmedin Jemal, Farhad Islami. Area deprivation, rurality, healthcare utilization, quality of life, and health status among cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 797.
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Yehya, Amani, Alissar Monzer, Kevork Wakimian, Fatima Ghamlouche, Nour Saheb, Ayman Tawil, Hala Gali-Muhtasib, Deborah Mukherji, Albert El-Hajj i Wassim G. Abou-Kheir. "Abstract 5792: The novel therapeutic diiminoquinone exhibits anticancer effects on human prostate cancer cells in 2D and 3D in vitro models". Cancer Research 83, nr 7_Supplement (4.04.2023): 5792. http://dx.doi.org/10.1158/1538-7445.am2023-5792.
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Abstract Aim: To investigate the anticancer potential of the novel quinone DIQ on prostate cancer (PCa) cells in two-dimensional (2D) and three-dimensional (3D) in vitro. Methods: The anti-proliferative effect of DIQ on PC3 and DU145 PCa cell lines was determined in vitro by using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays. In addition, the potency of DIQ was tested on the formation and size of PCa cell-derived prostatospheres and organoids grown in a specialized 3D-culture system. Also, 3D organoids were established from fresh tissue samples representing different stages of PCa obtained from consented patients who underwent radical prostatectomy at the American University of Beirut Medical Center (AUBMC) according to appropriate Institutional Review Board (IRB) approval guidelines. This model was used to assess DIQ individualized tumor response on organoids growth and the effect was evaluated by quantifying the number of organoids formed (OFC) and calculating the average size (diameters). Results: Our results showed that DIQ significantly attenuated cell proliferation and viability in PC3 and DU145 PCa cell lines. DIQ also reduced the formation ability and size of PC3 and DU145 prostatospheres and organoids at sub-toxic doses of 1 µM. Potently, DIQ displayed a significant decrease in both the count and the size of the different patient-derived organoids as compared to their respective control. Conclusion: This study provides promising clues for the use of the novel anticancer therapeutic DIQ in targeting CSCs, findings that may have promising therapeutic implications for PCa patients. Citation Format: Amani Yehya, Alissar Monzer, Kevork Wakimian, Fatima Ghamlouche, Nour Saheb, Ayman Tawil, Hala Gali-Muhtasib, Deborah Mukherji, Albert El-Hajj, Wassim G. Abou-Kheir. The novel therapeutic diiminoquinone exhibits anticancer effects on human prostate cancer cells in 2D and 3D in vitro models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5792.
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Sebastian, Kimberley N., Hatice Gülçin Özer, Cory Howard, Laura Chadsey, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski i in. "Abstract 1620: Clonal hematopoiesis of indeterminate potential in the companion dog". Cancer Research 82, nr 12_Supplement (15.06.2022): 1620. http://dx.doi.org/10.1158/1538-7445.am2022-1620.
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Abstract Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a clinical entity of aging humans that is characterized by cancer-associated mutations in white blood cells, without evidence of overt neoplasia. CHIP has been associated with an increased risk of hematologic cancers, cardiovascular disease, and all-cause mortality. We hypothesized that somatic mutations in specific genes associated with human CHIP would be detectable in the blood of aged dogs not known to have hematologic disorders. Methods: DNA from paired germline and whole blood samples from 93 geriatric canine patients affected by solid cancer were subjected to targeted next generation sequencing. Impact of the variants was predicted using Polymorphism Phenotyping version 2 software (PolyPhen-2, Harvard). Clinical and demographic data were extracted from medical records. Results: Somatic variants were detected in peripheral blood of four (4.3%) female dogs aged 12-15 years. Affected genes were ASXL1, KIT, SF3B1, TET2, RUNX1, and PPM1D. The variant in PPM1D was a nonsense mutation, while the other five variants were single nucleotide non-synonymous variants in protein coding regions of the genes. Following analysis by PolyPhen-2, the single nucleotide variants in KIT and SF3B1 were predicted to be benign, while the variants in ASXL1, TET2, and RUNX1 were predicted to be damaging. Conclusion: These results support the presence of variants in CHIP-associated genes in geriatric canids at a frequency similar to that observed in people, and the dog represents the first species in which the genetic lesion of CHIP has been documented. Further investigations are needed to confirm the association of this genetic lesion with clinical outcomes. Citation Format: Kimberley N. Sebastian, Hatice Gülçin Özer, Cory Howard, Laura Chadsey, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski, Wenjuan Ma, William C. Kisseberth, John C. Byrd, Bonnie K. Harrington. Clonal hematopoiesis of indeterminate potential in the companion dog [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 1620.
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Griffin, Lyndsey, Latha Shivakumar, Leigh Boehmer, Savannah Dodson, Elana Plotkin, Sumanta Pal i Al B. Benson. "Abstract 999: Clinical trial matchmaking: Connecting sites to sponsors". Cancer Research 84, nr 6_Supplement (22.03.2024): 999. http://dx.doi.org/10.1158/1538-7445.am2024-999.
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Abstract Background: Oncology programs may encounter many challenges engaging in clinical trials. The Association of Community Cancer Center’s (ACCC) Community Oncology Research Institute (ACORI) conducted a survey to gather insights on barriers to clinical trial provision and implementation, patient recruitment, and identifying resources to support cancer programs. Methods: A survey of 29 questions was administered via Qualtrics. The survey focused on research-naïve sites (i.e., sites with little to no clinical research experience). Survey recipients were identified from ACCC’s membership database, and the survey was open from May 5 to October 10, 2023. One survey response was captured per program. Results: Of the 350 respondents, most were physicians, investigators, or oncology fellows (20%), directors/administrators (16%), patient navigators (12%), and APPs (12%). Responding programs were categorized as a comprehensive community cancer program (28%), community practice (26%), or academic medical center (21%). Eighty percent of respondents indicated their program currently conducts clinical research. The most common challenges included: patient recruitment (40%), limited staffing (36%), limited clinician time (32%), and lack of training in research administration and conduct (25%). The top 3 resources desired were communication about clinical research opportunities (65%), connections to clinical trial sponsors (49%), and clinical research coordinator training (41%). Conclusions: Survey results showed a clear need for improved communication regarding clinical research opportunities, connections to clinical trial sponsors, and education around clinical trial implementation. Data from this survey will be used to match sites with trial sponsors, especially sites that serve patients with cancer from under resourced geographic, socioeconomic, racial, and ethnic groups. Future efforts will seek to engage clinical trial sponsors in improving trial engagement and feasibility, workforce support, training, and clinical mentorship. Citation Format: Lyndsey Griffin, Latha Shivakumar, Leigh Boehmer, Savannah Dodson, Elana Plotkin, Sumanta Pal, Al B. Benson. Clinical trial matchmaking: Connecting sites to sponsors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 999.
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Chan, CY, AWI Lo, KO Lam, HY Ng, CC Chen, ML Lung i JMY Ko. "Abstract 5266: Prognostic role of molecular subclassification based on mutational profiling and tumor-associated neutrophil status in stage III colon cancer". Cancer Research 82, nr 12_Supplement (15.06.2022): 5266. http://dx.doi.org/10.1158/1538-7445.am2022-5266.
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Abstract The traditional prognostic prediction of colon cancer (CC) is based on the tumor-node-metastasis (TNM) system. This, however, is not adequate for clinical decision making due to the existence of inter-patient variations and heterogeneity of underlying molecular pathways. We aim to investigate the prognostic value of molecular subclassification utilizing i) tumor-associated neutrophil (TAN) status by immunohistochemical (IHC) staining; ii) microsatellite instability (MSI) and elevated microsatellite alteration at selected tetranucleotide repeats (EMAST) status by PCR-based microsatellite typing; and iii) next-generation sequencing (NGS) mutational profiling by deep sequencing of a 77-gene oncology panel. In the discovery phase, 130 pairs of archived normal and tumor formalin-fixed paraffin-embedded (FFPE) specimens of stage III CC patients were retrospectively recruited from Queen Mary Hospital. CC patients will be categorized into different molecular subclasses (MSCs) based on the status of TAN/MSI/EMAST/NGS mutational profiling molecular biomarkers. Kaplan-Meier analysis, log rank test, univariate and multivariate Cox proportional hazards regression analysis will be used for estimation of progression-free survival (PFS) and overall survival (OS) between the two groups of CC patients. We expect our data to provide useful information for improved stratification of stage III CC patients into high or low risk of recurrence and survival. Acknowledgement: The Health and Medical Research Fund (07181536) to JMYK. Citation Format: CY Chan, AWI Lo, KO Lam, HY Ng, CC Chen, ML Lung, JMY Ko. Prognostic role of molecular subclassification based on mutational profiling and tumor-associated neutrophil status in stage III colon 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 5266.
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Yueh, Po-Fu, Fei-Ting Hsu i Keng-Li Lan. "Abstract 5067: Identify the combination efficacy and immune regulation of Abraxane combines with human IL-15 albumin binding domain fusion protein on pancreatic ductal adenocarcinoma animal model". Cancer Research 82, nr 12_Supplement (15.06.2022): 5067. http://dx.doi.org/10.1158/1538-7445.am2022-5067.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the hardest medical challenge in the world. Nab-paclitaxel is significantly more effective chemotherapy drugs than paclitaxel formulated as Cremophor EL. In this study, we reported the immune effect of Abraxane to combine with our new design recombinant human IL-15 fused with albumin binding domain (hIL-15-ABD) on subcutaneously Panc02 and orthotopically KPC PDAC animal models. In our results, the combination treatment greatly reduced the subcutaneous tumor growth in Panc02 and KPC bearing models, compared with vehicle group. Furthermore, the combinational therapy successfully buildup the anticancer immunity microenvironment (TME) through increasing the activation of effector cells, such as of NK cells (CD3-/CD49b+/NK1.1+) and CD8+ T (CD8+/IFN-γ+/IL-2+) cells. Moreover, combination therapy may also decrease the accumulation of immunosuppressvie cells such as MDSCs (CD11b+/Gr-1+) and Tregs (CD4+/CD25+/Foxp3+). The combination of Abraxane and hIL-15-ABD were also reduced the NF-κB-mediated immunosuppressive markers, including IDO, Foxp3 and VEGF. In conclusion, Abraxane combined with hIL-15-ABD enhanced immue effector cells involved in both innate and adaptive immunities, reduced the TME’s immunosuppressive cells, and displayed superior inhibitory effect on both subcutaneous and orthotopic syngeneic murine pancreatic ductal adenocarcinoma models than that of either monotherapy. These results suggest that combinational therapy of Abraxane and hIL-15-ABD could be a promising treatment stratedgy for PDAC. Citation Format: Po-Fu Yueh, Fei-Ting Hsu, Keng-Li Lan. Identify the combination efficacy and immune regulation of Abraxane combines with human IL-15 albumin binding domain fusion protein on pancreatic ductal adenocarcinoma animal model [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 5067.
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Luo, Jian-Hua, Silvia Liu i Yan-Ping Yu. "Abstract LB150: Clinical outcome prediction of prostate cancer using machine learning based on fusion gene detection". Cancer Research 82, nr 12_Supplement (15.06.2022): LB150. http://dx.doi.org/10.1158/1538-7445.am2022-lb150.
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Abstract Prediction of the clinical outcomes of prostate cancer remains a challenge. Recently, we discovered a panel of 8 fusion genes that occurred in aggressive prostate cancer. In order to make the fusion gene test clinically ready as a predictor, we have modified to test into a semi-quantitative Taqman QRT-PCR. In the funding period, Two hundred seventy-one prostate cancer samples with clinical follow-up were collected from University of Pittsburgh Medical Center. In addition, 194 prostate cancer samples from University of Wisconsin, Madison and 108 prostate cancer samples from Stanford University were collected. Taqman QRT-PCRs were performed on these samples. Significant numbers of samples were found positive for some of these fusion genes. The expression of MAN2A1-FER, SLC45A2-AMACR, MTOR-TP53BP1 fusions are associated with prostate cancer recurrence in the UPMC cohort. Cross-validation showed that fusion gene model predicts up to 91% clinical outcomes of prostate cancer accurately. When cohorts of UPMC, Stanford and Wisconsin were combined, the accuracy is 74%. The combination of fusion with Gleason appeared to improve the overall accuracy from 77% (Gleason) to 92% (Gleason+fusion) in the UPMC cohort, and from 71% (Gleason) to 82% (Gleason+fusion) when all three cohorts are combined. When fusion combined with both pathology stage and Gleason, the accuracy was improved a little further: 93% accuracy in the UPMC cohort and 83% when all three cohorts are combined. In summary, fusion transcript prediction model may have a role in prostate cancer prognosis prediction and guiding the management of prostate cancer patients. Citation Format: Jian-Hua Luo, Silvia Liu, Yan-Ping Yu. Clinical outcome prediction of prostate cancer using machine learning based on fusion gene detection [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 LB150.
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Li, Linheng. "Abstract SY42-01: Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche". Cancer Research 82, nr 12_Supplement (15.06.2022): SY42–01—SY42–01. http://dx.doi.org/10.1158/1538-7445.am2022-sy42-01.
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Abstract Tumor-initiating stem cells shape microenvironment into an immunosuppressive barrier and a pro-tumorigenic nicheLinheng Li Stowers Institute for Medical Research, Kansas City MO 64110Kansas University of Cancer Center, Kansas City KS 66160 Accumulated evidence supports the concept that tumor-initiating stem cells (TSCs) are at the root of tumor/cancer and are largely responsible for the commonly observed resistance to chemoradiotherapy (CRT) and frequent relapse of disease. How a subset of TSCs, or therapy resistant TSC (TrTSC), survives and supports tumor regrowth post treatment is a fundamental biological question and clinically unsolved problem. Recently, we utilized single-cell RNA-sequencing to identify therapy resistant TSCs (or TrTSCs) in mouse models of CRT-challenged intestinal adenoma, followed by bioinformatics analysis to reveal the bidirectional crosstalk that occurs between TSCs and the tumor microenvironment (TME). The results of the analysis indicate that TSCs shape the TME into an immunosuppressive barrier. Particularly, TrTSCs recruit tumor-associated monocytes and macrophages (TAMMs), which in turn, via Cox-2 dependent prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, induce Akt-mediated phosphorylation of β-catenin and thus enhance the β-catenin activity. Furthermore, we show that enhanced β-catenin signaling upregulates multiple immune-checkpoint genes, thus empowering the immune escape capabilities of TSCs. Taken together, overcoming both the extrinsic immunosuppressive barrier and intrinsic immune escape has the potential to increase the efficacy of checkpoint inhibition therapies against cancers in the future. Citation Format: Linheng Li. Tumor-initiating stem cells shape the microenvironment into an immunosuppressive barrier and a pro-tumorigenic niche [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 SY42-01.
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Yeo, Chang Dong, Hye Seon Kang, In Kyoung Kim, Sang Haak Lee i Jin Woo Kim. "Abstract 6757: Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation". Cancer Research 83, nr 7_Supplement (4.04.2023): 6757. http://dx.doi.org/10.1158/1538-7445.am2023-6757.
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Abstract Background: Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance were not identified. Patients and Methods: The present study used the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from 2018 to 2021. In all, 51 NSCLC patients that were treated with durvalumab consolidation therapy after definitive CCRT. Early relapse was considered if it occurred within 6 months of starting initial durvalumab therapy. Results: During study period, 15 (29.4%) relapsed among 51 included patients. Median time from initial therapy of durvalumab to progression was 107.73 ± 47.69 days in early relapse group. In mutivariate analysis, younger age (HR 0.713, 95% CI 0.572-0.888, P=0.003), higher pack years (HR 1.311, 95% CI 1.109-1.549, P=0.001), non-COPD (HR 0.030, 95% CI 0.001-0.677, P=0.027), anemia (HR 23.30, 95% CI 2.030-267.48, P=0.011) and stage IIIC (vs. stage IIIA) (HR 17.890, 95% CI 1.997-160.243, P=0.010) were independent predictive factors for early relapse during durvalumab consolidation therapy. Conclusion: Younger age, higher pack years, non-COPD, anemia and stage IIIC were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals. Citation Format: Chang Dong Yeo, Hye Seon Kang, In Kyoung Kim, Sang Haak Lee, Jin Woo Kim. Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6757.
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Du, Wu, Zhilin Tu, Dekun Qin, Haibo Li, Jingyi Duan, Shijuan Liu, Meng Zhang i in. "Abstract LB179: Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer". Cancer Research 84, nr 7_Supplement (5.04.2024): LB179. http://dx.doi.org/10.1158/1538-7445.am2024-lb179.
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Abstract Breast cancer remains an unmet medical need. It has become the most occurring and deadliest cancer for women globally. Estrogen receptor (ER) is expressed in 75% of breast cancers and has the key role in tumorigenesis and progression of ER+ breast cancers. Endocrine treatments that target ER are the mainstay therapies for the ER+ breast cancers, yet drug resistance unavoidably develops due to mutations in the ER gene. The ER-targeting proteolysis targeting chimera (PROTAC) degrader is an emerging new modality that interrupts the ER signaling through degradation of ER and offers unprecedented potential for solving the endocrine resistance. We have discovered HP568, an ER-targeting PROTAC that is highly potent against both the wild-type ER and ER mutants. HP568 has a favorable ADME profile that is superior to known competitor ER-targeting PROTAC. In the head-to-head comparison efficacy studies, HP568 has demonstrated the dose-dependent and superior efficacy that is well consistent with the drug exposure profile and PD biomarkers. HP568 also shows a synergetic effect in combination with a CDK4/6 inhibitor. HP568 is clean in the secondary pharmacology profiling, and well tolerated in animal tox studies. HP568 is under the preclinical development and has the potential to be the best-in-class ER-targeting degrader. HP568 structure will not be disclosed. Citation Format: Wu Du, Zhilin Tu, Dekun Qin, Haibo Li, Jingyi Duan, Shijuan Liu, Meng Zhang, Zhenyan Nie, Zhihui Yuan, Jing Li, Xinghai Li. Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB179.
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Turner, Kea, Jessica Y. Islam, Yessica C. Martinez, Omar Garcia Rodriguez, Diane Rodriguez Irlanda, Oliver T. Nguyen, Heather S. L. Jim i Kathleen M. Egan. "Abstract 4374: Patient provider communication about the use of medical cannabis for cancer symptoms". Cancer Research 83, nr 7_Supplement (4.04.2023): 4374. http://dx.doi.org/10.1158/1538-7445.am2023-4374.
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Abstract There has been limited study of patient-provider communication regarding medical cannabis for cancer symptoms. To address this gap, this study assesses the prevalence of patient-provider communication about the use of medical cannabis for cancer symptoms. Three types of communication are examined: 1) patient-provider discussions; 2) provider recommendations; and 3) provider instructions for how to use medical cannabis. We administered a survey from August to November 2021 with adult cancer patients who completed treatment from July 2017 to December 2019 at a National Cancer Institute designated Comprehensive Cancer Center; 1,592 individuals participated (response rate: 17.6%). About half of participants were female (52.1%). The age distribution of participants included 18-44 (9.4%), 45-54 (12.8%), 55-64 (25.3%), 65-74 (35.4%), and 75 and above (17.3%). Participant’s racial and ethnic background included Hispanic/Latinx (6.5%), African American/Black (4.0%), Asian American (1.0%), additional or multiple racial categories (3.5%), and White (91.5%). About a third (33.5%) of participants (530/1584) reported discussing medical cannabis for cancer symptoms with a healthcare provider. Participants who had discussed cannabis with a provider reported discussions with multiple providers including their oncology physician (62.3%), primary care provider (45.7%), oncology advanced practice provider (APP) (34.3%), dietician (7.4%), pharmacist (2.8%), and other healthcare provider (34.3%). Fewer (15.6%) participants (248/1592) reported receiving a recommendation for medical cannabis from a healthcare provider for their cancer symptoms. Participants who had received a recommendation reported recommendations from their oncology physician (32.7%), primary care provider (26.6%), oncology APP (13.7%), dietician (4.8%), pharmacist (1.6%), and other healthcare provider (56.9%). About a third (33.7%) of participants (537/1592) reported using medical cannabis during their cancer treatment and most often reported receiving instructions on how to use cannabis from no one (36.9%) or from a cannabis store or dispensary worker (23.8%). Less commonly, participants reported receiving instructions from their healthcare provider including their primary care provider (3.7%), oncology APP (2.0%), oncology physician (1.5%), pharmacist (<1%), or dietician (<1%). Based on this survey, about a third of cancer patients discuss medical cannabis with a healthcare provider but fewer receive a recommendation and/or instructions for how to use medical cannabis from a healthcare provider. Additional interventions may be needed to ensure that cancer patients interested in or currently using medical cannabis receive guidance from oncology care providers. Citation Format: Kea Turner, Jessica Y. Islam, Yessica C. Martinez, Omar Garcia Rodriguez, Diane Rodriguez Irlanda, Oliver T. Nguyen, Heather S.L. Jim, Kathleen M. Egan. Patient provider communication about the use of medical cannabis for cancer symptoms. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4374.
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Florez, Narjust, Inas Abuali, Ana Velazquez, Coral Olazagasti, Idalid Franco, Shruti Patel, Cristiane Bergerot i in. "Abstract B084: The Florez Lab at Dana-Farber Cancer Institute: Improving the care of vulnerable populations and supporting trainees from underrepresented groups in medicine". Cancer Epidemiology, Biomarkers & Prevention 32, nr 1_Supplement (1.01.2023): B084. http://dx.doi.org/10.1158/1538-7755.disp22-b084.
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Abstract Background: Racial and ethnic minorities have well-established disparities in cancer prevention, detection, treatment, and survival. A diverse oncology workforce improves the gap in cancer care for vulnerable populations. However, physicians, researchers, and others who are Underrepresented in Medicine (UIM) face unique challenges in obtaining mentorship and sponsorship, and there is a lack of safe spaces for them to thrive, forcing many to leave medicine entirely. To further efforts in improving the care of vulnerable populations and to create a welcoming environment for UIM medical trainees, the Florez Lab (formerly known as the Duma Lab) was founded by Dr. Narjust Florez in 2019 at the University of Wisconsin. Subsequently, Dr. Florez moved to Dana-Farber Cancer Institute and expanded the lab’s reach. Here, we describe the history and legacy of our innovative group. Methods: The Florez Lab is composed of 39 members, mostly UIM from different backgrounds and locations; members range from college students to faculty. It began as an all-female team but now includes #HeforShe member allies. Several members joined as trainees, but are now junior faculty at NCI designated cancer centers and pay it forward by mentoring the next generation of the Florez Lab. We focus on social justice issues in medicine, including discrimination and gender bias in academic and clinical medicine, global oncology, and cancer health disparities, with a focus on thoracic oncology. Results: To date, the Florez Lab has secured research funding from several institutions and organizations, and has published 15 original articles, 11 editorials, 4 review articles, and 2 book chapters in addition to over 20 poster presentations at national and international conferences. Members have presented research findings at a wide array of national and international conferences, including the American Society of Clinical Oncology (ASCO) Annual Meeting and the World Conference on Lung Cancer, and the American Association for Cancer Research (AACR) Annual Meeting. The lab collaborates with multiple organizations, including the COVID-19 and Cancer Consortium (CCC19), ASCO Health Equity Committee, and the Lancet Commission: Women & Cancer. The lab is far-reaching; the #DumaLab and #FlorezLab hashtag is used on Twitter to amplify published work and advocacy efforts in improving the diversity of the oncology workforce and clinical trial enrollment. In 2021 the Florez Lab began a collaboration with Medscape and is the first lab to have a dedicated column, where we discuss issues related to social justice in medicine and cancer health disparities; the column has reached over 60,000 readers in less than one year. Conclusion: The success of the Florez Lab illustrates the importance of providing opportunities for, supporting, and amplifying the success of UIM trainees. Results indicate that the collaboration of UIM trainees is productive, meaningful, and necessary. Efforts should be made to continue supporting UIM trainees from all backgrounds and levels. Citation Format: Narjust Florez, Inas Abuali, Ana Velazquez, Coral Olazagasti, Idalid Franco, Shruti Patel, Cristiane Bergerot, Paulo Bergerot, Enrique Soto Pérez, Carolina Bernabe-Ramirez, Lauren Kiel. The Florez Lab at Dana-Farber Cancer Institute: Improving the care of vulnerable populations and supporting trainees from underrepresented groups in medicine [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B084.
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Zeb, Sabaoon, Khudeja Salim, Hina Zamir, Madina Shirdel, Momal Agha, Asma Qudrat, Sajjad Ahmad i in. "Abstract 6316: Minimizing ineffective treatment using an in vitro patient derived cancer cell screening platform for local oral squamous cell carcinoma patients in Pakistan". Cancer Research 82, nr 12_Supplement (15.06.2022): 6316. http://dx.doi.org/10.1158/1538-7445.am2022-6316.
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Abstract According to GLOBOCAN’s 2020 report, in Pakistan, lip and oral cavity is the second most prevalent cancer with a low survival rate due to late detection and ineffective treatment regimens. To reduce ineffective treatment, this study aims to develop a cost-efficient in vitro drug screening platform using patient-derived primary cell lines to identify effective drugs against Oral Squamous Cell Carcinoma (OSCC) patients. Chemotherapeutic drugs to be screened were identified from NCCN guidelines as well as the local standard of care after oncologists from three tertiary care hospitals. These included 15 chemotherapeutic drugs along with 14 combinations. For this pilot study, tumor biopsies were collected, after relevant IRB approvals from consenting patients as part of the Oral Cancer Genomics Study project. Patient-derived primary cell lines were generated from tumor biopsies of 20 local OSCC patients recruited at Rehman Medical Institute and Hayatabad Medical Complex, Peshawar, Pakistan. Primary cell lines were derived from tumor biopsies within 30 minutes of resection and propagated till confluency using an optimized DMEM protocol. The readouts of our screen include cell viability, cell proliferation and cytotoxicity. This pilot screen presents a first of its kind dataset of the performance of drugs and drug combinations in primary cell lines derived from the tumors of local patients in Pakistan. This is not just an ideal platform to test novel and re-purposed drugs but also to develop into a service for personalized treatments, minimizing ineffective treatment and improving patient outcomes. Citation Format: Sabaoon Zeb, Khudeja Salim, Hina Zamir, Madina Shirdel, Momal Agha, Asma Qudrat, Sajjad Ahmad, Muhammad Faisal, Muhammad Atif Munawar, Muhammad Mushtaq Khattak, Mushtaq Ahmad, Zubbair Durrani, Faisal F. Khan. Minimizing ineffective treatment using an in vitro patient derived cancer cell screening platform for local oral squamous cell carcinoma patients in Pakistan [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 6316.
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Hsieh, Kang Lin, Bor-Sheng Ko, Xiaoqian Jiang, Teng-Jen Chang i Yu-Fen Wang. "Abstract 1026: The costs of waiting to get treated for new AML patients: Medical expenditures, mortality rate, and length of hospital stay". Cancer Research 82, nr 12_Supplement (15.06.2022): 1026. http://dx.doi.org/10.1158/1538-7445.am2022-1026.
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Abstract Introduction: We studied the association of waiting time from diagnostic Acute Myeloid Leukemia (AML) tests to initial treatment and medical expenditures, length of hospitalization, and survival rates for new AML patients. Method: We extracted 3,976 new AML patients from Optum’s de-identified Clinformatics࣪ Data Mart Database, a data warehouse of adjudicated commercial and medicare advantage claims. Their waiting days from standard diagnostic testings to the initial AML-specific treatment as the risk factor. Medical expenditures occurring within 6 months, 1 year, and 2 years after the index AML diagnosis was measured for the patients’ financial wellbeing, along with the survival rate and the length of hospital stay. We compared these outcomes for patients falling in each waiting time category. Different types of expenditures, including inpatient and outpatient costs for patients with different waiting lengths were compared. Results: For patients with moderate lengths of waiting time, medical expenditure and mortality rate increases and length of hospital stay decreased with waiting time. Within 2 years after the index AML diagnosis, the average expenditures per day goes from $4,803 for patients waiting for 0-2 days to $7,489 for patients waiting for 1-2 weeks, while the survival rate goes from 42.8% to 28.1% and the average length of stay goes from 45.6 days to 35.0 days. The increment in medical expenditure is mostly accounted for by outpatient costs, but is off-set by inpatient costs. The patterns for medical expenditure and survival rate reverse as waiting time becomes severe (3-4 weeks). Similar reverse is not observed for length of stay. Conclusion: The waiting time between AML diagnostic tests and initial treatments is associated with higher medical expenditure and higher mortality rate for moderate waiters. Our findings suggest that reducing waiting time has strong potential in improving AML patients’ survival and financial sustainability. Medical expenditure, survival rate, and length of hospital stay within 2 years by waiting time Medical expenditure per day ($) 2-yr Survival rate (%) Length of hospital stay (days) <2d 4803 42.8 45.6 2-7d 5008 30.3 36.6 7-14d 7489 28.1 33.9 14-28d 4174 29.8 30.4 >28d 2224 51.0 35.0 Citation Format: Kang Lin Hsieh, Bor-Sheng Ko, Xiaoqian Jiang, Teng-Jen Chang, Yu-Fen Wang. The costs of waiting to get treated for new AML patients: Medical expenditures, mortality rate, and length of hospital stay [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 1026.
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Han, Younghun, Katherine A. McGlynn, Jinyoung Byun, Matthew A. Cooley, Manal M. Hassan, Christopher I. Amos i Lewis R. Roberts. "Abstract 5228: Genome-wide association study and LD score regression analysis for cholangiocarcinoma". Cancer Research 83, nr 7_Supplement (4.04.2023): 5228. http://dx.doi.org/10.1158/1538-7445.am2023-5228.
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Abstract Cholangiocarcinoma (CCA) is a rare and aggressive cancer of the bile ducts, with a poor prognosis and limited treatment options. CCA are classified as intrahepatic and extrahepatic based on anatomical location. CCA are often diagnosed at an advanced stage because there are no effective tools for early detection. Although genome-wide association studies (GWASs) have discovered many genome-wide significant contributing risk loci, the genetic underpinning of cholangiocarcinoma remains poorly understood. To date, there is no cholangiocarcinoma-specific GWAS. We conducted GWAS of cholangiocarcinoma in 9,648 individuals of European ancestry using TOPMed reference panel. The putative associations in or near THSD7A on chromosome 7 (OR=2.61, P=7.13 × 10−8), ZBTB16 on 11 (OR=0.16, P=6.02 × 10−8) for non-PSC-related CCA, PUM3 on 9 (OR=10.74, P=6.12 × 10−8), AGBL1 on 15 (OR=2.08, P=5.67 × 10−8) for PSC-related CCA, and LINC02506 on 4 (OR=0.16, P=8.83 × 10−9) for extrahepatic CCA. We also implemented linkage disequilibrium score regression (LDSR) analysis to quantify the genetic correlation between phenotypes using publicly available GWAS summary statistics. Our study aimed to identify possible clinical and epidemiological traits associated with CCA. We identified numerous biomarkers, medical conditions, environmental and behavioral traits, and physical measurements showing high heritability, which is the proportion of phenotypic variance explained by all SNPs included in the analysis, and pairwise genetic correlation with CCA and other CCA subtypes. Elevations of selected biomarkers such as alkaline phosphatase, cystatin C, HbA1c, monocyte count, and white blood cell count show a positive genetic association with CCA in European-ancestry population. Also, autoimmune-mediated conditions show a strong positive genetic association with CCA, non-PSC related CCA, and intrahepatic CCA. The GWAS of CCA and CCA subtypes revealed potential genetic susceptibility associations and will allow us to compare the genetic architecture underlying CCA and other diseases of the bile ducts such as primary sclerosing cholangitis and liver cancer. LDSR provided an improved understanding of the genetic architecture between CCA and potential comorbid conditions and biomarkers. Mendelian randomization analysis will be needed to elucidate the causal relationship between CCA and traits of interest. Citation Format: Younghun Han, Katherine A. McGlynn, Jinyoung Byun, Matthew A. Cooley, Manal M. Hassan, Christopher I. Amos, Lewis R. Roberts, The International Consortium for the Genetics of Biliary Tract Cancers. Genome-wide association study and LD score regression analysis for cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5228.
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Washington, Samuel L., Kim F. Rhoads, Peter R. Carroll, Salma Shariff-Marco i June M. Chan. "Abstract 815: Leveraging clinical workflow for rapid integration of social needs assessment in a urologic oncology clinical practice". Cancer Research 84, nr 6_Supplement (22.03.2024): 815. http://dx.doi.org/10.1158/1538-7445.am2024-815.
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Abstract Introduction: Social determinants of health and resulting social needs are known to impact cancer care, yet characterization of social needs within a specific clinic’s population remains in its infancy. We aim to characterize early findings from social needs screening in patients seen in a tertiary urologic oncology clinic. Methods: Screening was conducted using survey questions about specific domains of social needs (e.g., financial strain, unmet transportation needs, and food insecurity) that were integrated into new patient and annual follow-up questionnaires for all patients seen within a urologic oncology faculty clinic, starting in January 2023. Screening items were rapidly implemented into workflow by taking advantage of existing processes. Clinical and demographic data and screening responses were abstracted from the electronic medical record. Summary statistics were calculated. P value<0.05 was deemed statistically significant. Results: A total of 2305 patients were included (4% Non-Hispanic Black, 11% Asian American, 8% Latinx, and 63% Non-Hispanic White). Responses increased from 30 in January to 399 in October. Respondent mean age was 67 years [standard deviation (SD) 12.3] with 87.8% identifying as male. Roughly 13% screened positive for at least one social need (one positive 8.1%, two positive 3.4%, three positive 1.2%) with variations by domain [transportation 3.6%, food insecurity 5.4%, 10.2%] and race and ethnicity (Figure 1, p<0.001 for all). Conclusions: By leveraging the existing clinical workflow, rapid uptake of social needs screening demonstrates variations by social needs domains and race and ethnicity within a urologic oncology patient population. These efforts represent institutional action towards characterizing the burdens faced by our patient population and inform the design of interventions to address social needs within the catchment area, to improve clinical care and clinical trial participation. Citation Format: Samuel L. Washington, Kim F. Rhoads, Peter R. Carroll, Salma Shariff-Marco, June M. Chan. Leveraging clinical workflow for rapid integration of social needs assessment in a urologic oncology clinical practice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 815.
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Mosha, Maua, Jennifer Mayer i Ernest K. Amankwah. "Abstract 4365: Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients". Cancer Research 83, nr 7_Supplement (4.04.2023): 4365. http://dx.doi.org/10.1158/1538-7445.am2023-4365.
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Abstract The influence of comorbidities at index diagnosis on outcomes of pediatric leukemia and lymphoma is not well established. We evaluated the association between medical comorbidities and pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) outcomes in a retrospective cohort study using electronic health records from the TriNetX Research Network Database, a global de-identified federated health research network. Study participants included pediatric (≤21 years) patients newly diagnosed with ALL or LL from July 2009-June 2019 and followed through June 2022. The main outcomes included progression/relapse, toxicity, overall mortality and cancer-specific mortality. Comorbidities included chronic lung disease; congenital heart disease; neurologic, immune, hematologic, vascular and genetic disorders; renal disease; gastrointestinal disease; prematurity and hepatobiliary disease. Patients with any comorbidity were matched with patients with no comorbidity on age at diagnosis, gender, race/ethnicity, and treatment using propensity score matching. We identified 5,375 patients diagnosed with ALL/LL with comorbidities and 5,375 without comorbidities after propensity score matching. The mean age at diagnosis was 9.7 years (standard deviation=6.2). A higher proportion of the patients were male (56.9%), White (63.6%) and Not Hispanic or Latino (63.4%). Patients diagnosed with comorbidities had a higher risk for progression/relapse (73% vs 51%; Relative Risk, RR=1.42, 95% confidence interval (CI)=1.38-1.47) and treatment related toxicity (80% vs 50%; RR=1.59, 95% CI=1.54-1.64), compared to patients diagnosed with no comorbidities. Similarly, overall mortality (Hazard ratio, HR=1.62, 95% CI=1.37-1.91) and cancer-specific mortality (HR=4.39, 95% CI=2.28-8.46) were higher among patients diagnosed with comorbidities than those without comorbidities. Comorbidities among patients diagnosed with ALL/LL is associated with poor outcomes independent of treatment and thus targeted interventions for the proper management of these patients are needed to improve outcomes. Citation Format: Maua Mosha, Jennifer Mayer, Ernest K. Amankwah. Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4365.
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Bittoni, Marisa A., David Carbone i Randall Harris. "Abstract 2213: Vaping, smoking and lung cancer: A case-control study". Cancer Research 84, nr 6_Supplement (22.03.2024): 2213. http://dx.doi.org/10.1158/1538-7445.am2024-2213.
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Abstract Introduction: Nicotine exposure through the use of electronic delivery systems (vaping) has been found to elevate the risk of certain conditions of the lungs, e.g., vaping associated lung injury. However, the potential impact of vaping on lung cancer risk remains largely unexplored. We, therefore, examined the association of vaping and cigarette smoking with lung cancer risk in a case-control study conducted at The Ohio State University in Columbus, Ohio. Methods: Medical records examined from the James Cancer Hospital and Solove Research Institute revealed 4,975 cases with newly diagnosed, pathologically confirmed lung cancer during 2013-2021. These cases were compared to 27,294 controls without cancer that were group-matched on a 5:1 ratio to cases by age, gender, race and year of ascertainment. Descriptive statistics were calculated, and logistic regression analyses were performed to assess the associations between vaping, smoking and lung cancer. Results: The lung cancer cases in this study were 55% male, 88% white, with mean age at diagnosis of 62 years. The adjusted odds ratio (OR) for individuals who reported vaping and smoking was OR=21.1 (95% CI=17.1, 26.1) versus OR=6.3 (95% CI=5.8, 6.8) for smoking only. Estimates for gender and histologic cell type of lung cancer, e.g., pulmonary adenocarcinoma, squamous cell carcinoma and small cell carcinoma, were consistently over threefold higher for vaping and smoking compared to smoking only (p<0.001), and the vaping effect persisted even after adjustment for comorbidities, COPD and cardiovascular disease. Conclusion: Adjusted estimates of odds ratios (OR) revealed over threefold higher risk of lung cancer among individuals who had vaped and smoked compared to individuals who only smoked. Our results suggest that the addition of vaping to smoking greatly accelerates the risk of developing lung cancer. Future studies are needed to further confirm these results. Citation Format: Marisa A. Bittoni, David Carbone, Randall Harris. Vaping, smoking and lung cancer: A case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2213.
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Fine, Bobbie Dean, Shelbie Stahr, Lora J. Rogers, Gail A. Runnells, Tung-Chin Chiang i Lihchyun J. Su. "Abstract 1443: Environmental heavy metal toxicity and mammographic breast density in a Mississippi Delta southern state". Cancer Research 82, nr 12_Supplement (15.06.2022): 1443. http://dx.doi.org/10.1158/1538-7445.am2022-1443.
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Abstract Importance: Increased mammographic density (MD) is a strong independent risk factor for breast carcinoma. Ubiquitous environmental heavy metal (HM) exposure/toxicity appears pro-carcinogenic in several human cancers. However, studies in the current scientific literature have not elucidated specific connections between HM exposure and mammographically detected increases in breast density. Objective: To determine whether increases in heavy metals (ie, chromium, arsenic and cadmium) measured in urine as a biomarker for long-term exposure, associate with increased MD in a female study cohort in Arkansas. Design, Setting, Participants: One hundred thirty-nine participants in the Arkansas Rural Community Health (ARCH) study cohort, recruited through a mobile mammography unit at baseline, were included in this pilot study. Demographic/health history questionnaire data, urine, blood and saliva samples and incident mammograms classified by BI-RADS were ascertained after informed consent. Study protocol was approved by the Institutional Review Board at the University of Arkansas for Medical Sciences (UAMS). Main Outcome and Measures: Urinary chromium, arsenic and cadmium levels were determined using inductively coupled plasma mass spectrometry. The concentrations of HM were adjusted for urinary creatinine and specific gravity and the results categorized into tertiles. Multivariable logistic regression models were used to evaluate the association between HM exposure and MD. Association of both continuous and categorical variables were examined. Confounding variables in the multivariable models including age, race, BMI, age at menarche and smoking history were determined by a priori knowledge and statistical assessment. Results: Odds ratios (OR) and 95% confidence intervals (CI) for the association between each tertile of HM exposure and MD were used for the assessment. For the unadjusted model, increasing ORs for MD were noted with increased levels of both Chromium and Arsenic exposure. Increased ORs for MD were observed with increased levels of Chromium, Arsenic and Cadmium exposure in the multivariable adjusted model. However, none of these associations demonstrated statistical significance in this limited pilot study. Conclusion: Positive associations between HM exposure and MD were noted after adjusting for age, sex, BMI, age at menarche and smoking history in this pilot study. However, the association did not reach statistical significance at α = 0.05. Citation Format: Bobbie Dean Fine, Shelbie Stahr, Lora J. Rogers, Gail A. Runnells, Tung-Chin Chiang, Lihchyun J. Su. Environmental heavy metal toxicity and mammographic breast density in a Mississippi Delta southern state [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 1443.
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Beeghly-Fadiel, Alicia, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel i Marta A. Crispens. "Abstract 3228: Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival". Cancer Research 82, nr 12_Supplement (15.06.2022): 3228. http://dx.doi.org/10.1158/1538-7445.am2022-3228.
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Abstract Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship. Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis. Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94). Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed. Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [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 3228.
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Schafer, Cara C., Jiji Jiang, Sally Elsamanoudi, Darryl Nousome, Denise Young, Yingjie Song, Isabell Sesterhenn, Gregory Chesnut i Shyh-Han Tan. "Abstract 3805: Immunologic transcript and cell type evaluation of prostate tumors from a military cohort of African American and Caucasian American patients". Cancer Research 82, nr 12_Supplement (15.06.2022): 3805. http://dx.doi.org/10.1158/1538-7445.am2022-3805.
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Abstract Background: Health and racial disparities in prostate cancer place African American (AA) men at greater risk of developing and having a poorer outcome from the disease, especially at a younger age compared to Caucasian American (CA) men. This incidence is also reflected among active-duty service members, and patient biospecimens obtained from an equal access healthcare setting at the Walter Reed National Military Medical Center provide a valuable resource for the evaluation of cancer health disparities. The objectives of this study are to identify immunobiological differences influencing prostate cancer disparities and to elucidate the immune cell profiles of patient tumors associated with advanced disease. Methods: Patients provided written consent to both biospecimen and clinical database collection under IRB-approved protocols. Fresh frozen tumor biopsy tissues were collected ex vivo, following radical prostatectomy. Total tumor RNA was amplified by PCR-based multiplexed target enrichment, and barcode-tagged transcripts were quantified using NanoString technology. Raw and relative abundances of immune cells were determined using published deconvolution algorithms. Differential expression of immune-related genes and cell type contrasts were evaluated for correlation with clinico-pathologic features. Results: Genes regulating metabolism and innate immune responses were differentially expressed between AA and CA prostate tumors (AA n=26, CA n=25). Comparing high vs. low expression of each of these top genes, two were associated with biochemical recurrence (BCR)-free survival. Most immune cell subtypes did not differ significantly between AA and CA, but mast cells appeared to be enriched within AA tumors. When cell types were stratified by clinical and pathologic variables, we identified consistent trends in immune cell content that changed with increasing diagnostic age, PSA group, Grade Group, Gleason Sum, and with disease progression as defined by future development of BCR and/or metastasis. Conclusions: Attention should be directed toward observed immunobiological differences based on race and other clinico-pathologic factors at the time of radical prostatectomy. Patient-centered studies mindful of existing health disparities will aid in diagnostic and therapeutic strategies that are inclusive of an increasingly diverse US and US military population. Disclaimer: The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of the USUHS, HJF, the DoD or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. IRB protocol: DBS.2019.032 (Ref Number 930187) Citation Format: Cara C. Schafer, Jiji Jiang, Sally Elsamanoudi, Darryl Nousome, Denise Young, Yingjie Song, Isabell Sesterhenn, Gregory Chesnut, Shyh-Han Tan. Immunologic transcript and cell type evaluation of prostate tumors from a military cohort of African American and Caucasian American patients [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 3805.
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Barakzai, Madina, Shagufta Rehmat i Faisal F. Khan. "Abstract 6337: Assessing genomic literacy among medical trainees and practitioners in Pakistan". Cancer Research 82, nr 12_Supplement (15.06.2022): 6337. http://dx.doi.org/10.1158/1538-7445.am2022-6337.
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Abstract Genomic literacy has a significant impact on the successful application and deployment of new practices such as precision medicine. It can be described as the ability to achieve, process, understand, and apply genomic knowledge to health-related decision-making. The aim of this study is to assess the level of genomic literacy, including the knowledge of genetic testing, its outcomes, and its significance among medical trainees and practitioners in Pakistan. This study also offers recommendations for improving genomic literacy within the medical community in Pakistan. A cross-sectional study for which an online questionnaire was designed in the English language using Google Forms. The questionnaire was distributed among trainees and practitioners across Pakistan through online social media platforms. The survey comprised of 36 questions categorized into three sections namely demographics, quantitative questions, and knowledge section. A total of 219 medical professionals (56% trained in medicine while 44% in Dentistry) responded to the survey. Medical practitioners from 27 different cities across Pakistan participated in the survey but with a clear bias towards the city of Peshawar (90%). The majority of the participants (57.5%) were trainee medical officers. Most of the participants in this cohort were aware of genetics, the genome, and PCR technology but 74.9% were not familiar with genetic tests in their specialty. The mean total score for the multiple-choice questions among the participants was 62.5% graduates of medicine (65%) outperforming those in dentistry (59%). Participants were asked about their interest in further learning opportunities about genomics, for which 71% answered in affirmation, however, the remaining were not overly interested. Genomic literacy level can be considered satisfactory at the level of classical genetics, yet there is a clear need for training in molecular biology concepts such as protein synthesis, gene expression, and genome structure within the medical community. With a limited sample size and diversity of respondents, the subject warrants a broader survey to assess genomic literacy which can help in better planning for wider adoption of genomic testing in the medical community. Findings of this survey also highlight the need for assessing medical communities in other low-resource and underprivileged settings to help enhance our understanding and avoid a looming ‘genomics divide’. Citation Format: Madina Barakzai, Shagufta Rehmat, Faisal F. Khan. Assessing genomic literacy among medical trainees and practitioners in Pakistan [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 6337.
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Zhang, Li, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella i Dongxu Sun. "Abstract 1147: A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer". Cancer Research 82, nr 12_Supplement (15.06.2022): 1147. http://dx.doi.org/10.1158/1538-7445.am2022-1147.
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Abstract About 43,600 women in the U.S. are expected to die in 2021 from breast cancer. Triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, is diagnosed by exclusion of expression and/or amplification of three biomarkers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]).Characterized by a high risk of relapse (one half of patients with early stages experience recurrence), short overall survival and progression-free survival (life expectancy of few months after failure of first-line chemotherapy), TNBC represents a high unmet medical need. Galectin-3 plays multiple roles in tumor initiation and development via a variety of cellular processes, spanning from angiogenesis to tumor migration. Galectin-3 (Gal3) expression is induced in TNBC patients and highly correlates with poor survival, as shown by our and others’ bioinformatics analysis from public database. We recently discovered and patented a series of antibodies with high specificity and affinity for Gal3, one of which is currently tested in human volunteers. This clinical candidate has shown superior pharmacokinetic properties and clean toxicity profile in GLP studies on non-human primates. Here, we show that anti-Gal3 inhibit both anchorage dependent and independent growth of TNBC cells, as well as Gal3-induced escape from NK cell killing. Also, anti-Gal3 proved to be efficacious in in vivo studies, where TNBC cells were implanted in mammary fat pads of mice and tumor progression, measured as growth of primary mass and presence of metastatic nodules in the lungs, was followed during the two months of treatment. The results presented herein support the conclusion that our therapeutic modality could offer an alternative promising treatment of TNBC. Citation Format: Li Zhang, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast 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 1147.
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Hu, Taishan, Zhilin Deng, Honghai Li, Xiaochu Ma, Quanrong Shen, Lei Zhang, Peihua Sun, Ye Hua i Byran Huang. "Abstract 3943: Discovery of a novel menin-MLL inhibitor for potential treatment of MLLr leukemias and NPM1c AML". Cancer Research 82, nr 12_Supplement (15.06.2022): 3943. http://dx.doi.org/10.1158/1538-7445.am2022-3943.
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Abstract Rearrangement of the mixed lineage leukemia (MLL) gene occurs in up to 10% of acute leukemias and is particularly prevalent in infant acute leukemias (~80% of infant ALL cases). MLL-rearranged (MLLr) leukemia is one of the high-risk types of leukemia with aggressive nature, resistance to therapy, and high frequency of early relapse, and currently there are no targeted therapies for its treatment. So, there is huge unmet medical needs for MLLr leukemias. The protein protein interaction (PPI) between menin and MLLr is critical to the pathogenesis of MLLr-driven leukemias by deregulation of the HOXA and MEIS1 genes. It has been demonstrated by both preclinical and clinical studies that blockage of this PPI with menin inhibitors has potential therapeutic effects on MLLr associated acute leukemias. NPM1 mutation (NMP1c) is a frequently mutated gene found in AML, and NMP1 mutated AML depends on menin-MLL interaction for leukemogenesis. Given the fact that wild type MLL and MLLr have similar leukemogenesis-driven target genes like HOXA and MEIS1, as well as the same binding pocket on menin, it was therefore conceived that menin inhibitor could be useful to the treatment of NPM-mutated AML, which was again supported by both preclinical and clinical data. Herein, we would like to report the discovery of our proprietary menin inhibitor. Taking advantage of a couple of key interactions with menin protein, our compounds has relatively low molecular weight for a challenging PPI target, however, demonstrated comparable to or even better potency than those menin inhibitors in clinical trials. Besides in vitro pharmacology data, the DMPK, PK/PD and in vivo efficacy in animal model will be discussed too. Citation Format: Taishan Hu, Zhilin Deng, Honghai Li, Xiaochu Ma, Quanrong Shen, Lei Zhang, Peihua Sun, Ye Hua, Byran Huang. Discovery of a novel menin-MLL inhibitor for potential treatment of MLLr leukemias and NPM1c AML [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 3943.
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Liang, jiaqi, Dai Cheng, Yali Guo, xiaobin zhang, Xipan Liu, Jia Fu, Qiang Ding i in. "Abstract 2568: ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification". Cancer Research 82, nr 12_Supplement (15.06.2022): 2568. http://dx.doi.org/10.1158/1538-7445.am2022-2568.
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Abstract Cyclin E1 amplification is prevalent in cancers with high unmet medical need such as high grade serous ovarian cancer, stomach cancer and esophageal cancer. Cancer cell lines with high expression level of cyclin E1 gene exhibited profound sensitivity to CDK2 gene depletion, suggesting CDK2 selective inhibitors have the potential to treat patients harboring Cyclin E1 alterations. Here we report the development and preclinical characterization of ARTS-021, an orally bioavailable small molecule CDK2 selective inhibitor. In enzymatic assay against a panel of different CDKs, ARTS-021 potently inhibits the activity of CDK2/CyclinE1 complex with 50% inhibitory concentration (IC50) in the sub-nanomolar range, displaying superior selectivity against other CDKs (CDK1,4,6,7,9). Very low hit rate (S(10)=0.022, at 1uM) is observed when ARTS-021 is assessed in whole Kinome profiling, further revealing the selectivity of this compound. ARTS-021 also demonstrates potent CDK2 inhibition and selectivity against other CDK family members (CDK1,4,6,9) in a series of cellular assays. Consistent with genetic CDK2 dependence data, cell lines with CCNE1 amplification are particularly sensitive to ARTS-021. Double nanomolar ARTS-021 inhibits Rb phosphorylation and blocks G1/S transition, leading to cell growth arrest specifically in CCNE1 amplified cell lines. This CDK2 dependent anti-tumor activity is further validated in vivo, where daily ARTS-021 administration leads to tumor stasis in CCNE1 amplified but not wild type xenograft models. Taken together, these data demonstrate ARTS-021 as a promising CDK2 selective inhibitor with strong potential towards the development of effective therapies for CCNE1 altered cancer. Citation Format: jiaqi Liang, Dai Cheng, Yali Guo, xiaobin zhang, Xipan Liu, Jia Fu, Qiang Ding, Wen Xiong, Fang Li, Yaoyu Chen, Qing Sheng. ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification [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 2568.
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Zhao, Baiteng, Lei Wang, Haidong Liu, Suping Huang, Xiao Shang i Tae Han. "Abstract 1085: PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma models". Cancer Research 82, nr 12_Supplement (15.06.2022): 1085. http://dx.doi.org/10.1158/1538-7445.am2022-1085.
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Abstract PRO1184 is an antibody-drug conjugate (ADC) directed toward folate receptor alpha (FOLR1), a glycosyl phosphatidylinositol anchored membrane protein. FOLR1 is overexpressed in many cancers with unmet medical need, including ovarian, lung, and breast cancers, while normal tissue expression is limited. PRO1184 is comprised of a 1) human monoclonal antibody that selectively binds to FOLR1, 2) a cleavable, hydrophilic linker, and 3) exatecan, a topoisomerase 1 inhibitor. Upon binding to FOLR1 on the surface of malignant cells, PRO1184 is internalized and exatecan released through enzymatic cleavage of the linker. Exatecan blocks the ligation step of the cell cycle and generates DNA single- and double-strand breaks, which leads to cell death. The mechanism of action and clinical potential of PRO1184 was tested in a series of studies. PRO1184 bound selectively and specifically to FOLR1 with nM affinity. PRO1184 was efficiently internalized and demonstrated cytotoxicity against multiple cell lines, in vitro. In mouse carcinoma models, PRO1184 demonstrated robust anti-tumor activity across multiple tumor types that represent ovarian, non-small cell lung, and breast cancer. In addition, PRO1184 was more potent with greater tumor growth inhibition than that of a DM4-conjugated ADC. PRO1184 was tolerated at the 60 mg/kg dose level in cynomolgus monkeys and the safety profile was generally more favorable than that for a DXd-based ADC. The pharmacokinetics (PK) of PRO1184 were similar to that of the unconjugated parent antibody in rats. PRO1184 has the potential for a meaningful therapeutic window to provide an appropriate benefit to risk profile for patients with FOLR1-expressing cancers. Citation Format: Baiteng Zhao, Lei Wang, Haidong Liu, Suping Huang, Xiao Shang, Tae Han. PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, demonstrates robust anti-tumor activity in mouse carcinoma 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 1085.
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Zhu, Xiangzhu, Xiang Huang, Yinan Zheng, Wei Zhang, Lihua Shu, Reid Ness, Harvey J. Murff i in. "Abstract CT534: Magnesium treatment on the demethylation of chemokine (C-X-C motif) ligand 9 (CXCL9) gene, results from the personalized prevention of colorectal cancer trial". Cancer Research 82, nr 12_Supplement (15.06.2022): CT534. http://dx.doi.org/10.1158/1538-7445.am2022-ct534.
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Abstract Background: Chemokine ligand 9 (CXCL9), a T-cell chemoattractant, plays a critical role in regulating antitumor immunity in cancer immunotherapy, i.e., clinical responses to anti-PD(L)-1 treatment. Very recently, CXCL9 was identified as the strongest contributor to the “inflammatory clock of aging”, linked to age-related chronic inflammation. Due to the critical role of magnesium (Mg) in regulating inflammatory responses, this study aims to investigate the effect of Mg treatment on DNA methylation changes in CXCL9. Methods: The Personalized Prevention of Colorectal Cancer Trial conducted at Vanderbilt University Medical Center was a double-blind 2 × 2 factorial randomized controlled trial of 240 participants who completed the study. Participants aged from 40 to 85 years, had a daily calcium intake 700-2000 mg and calcium:magnesium intake ratio ≥2.6 based on the average of the two baseline 24-hour dietary recalls. Results: Among three CpG sites, a 12-week personalized dose of Mg supplementation marginally increased the 5-hydroxymethylcytosine methylation, a measure of active demethylation, at CpG site 04038163 (3'UTR of CXCL9 gene) by 7.0% compared to the placebo group (p=0.07). Although the overall effect was not significant or of borderline significance, Mg treatment significantly reduced the levels of 5-hydroxymethylcytosine by 3.7% at the CpG site 12793812 (body of CXCL9 gene) among those with aged 60 years or above (p=0.03). Conclusions: These findings indicate that Mg treatment modified the demethylation process in the CXCL9 gene, a critical regulator of immune responses and inflammation. Future studies are needed to examine if Mg treatment also changes the circulating levels of CXCL9. Citation Format: Xiangzhu Zhu, Xiang Huang, Yinan Zheng, Wei Zhang, Lihua Shu, Reid Ness, Harvey J Murff, Chang Yu, Martha J Shrubsole, Lifang Hou, Qi Dai. Magnesium treatment on the demethylation of chemokine (C-X-C motif) ligand 9 (CXCL9) gene, results from the personalized prevention of colorectal cancer trial [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 CT534.
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Barkholt, Pernille, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg i Patrick Schöffski. "Abstract 1547: The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies". Cancer Research 83, nr 7_Supplement (4.04.2023): 1547. http://dx.doi.org/10.1158/1538-7445.am2023-1547.
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Abstract Background: Soft tissue sarcoma (STS) is a complex family of rare malignancies with high unmet medical need. uPARAP is an endocytic receptor expressed at low levels on selected mesenchymal cell types, which internalizes fragments of collagen and transfers them to the lysosome for degradation. Besides its physiological role, uPARAP is considered a critical modulator of the tumor microenvironment. Here, for the first time, we explored the molecular epidemiology of uPARAP in sarcoma tissue to validate this receptor as target for the development of ADCs in this indication. Methods: uPARAP expression was assessed in STS-specific tissue microarrays by immunohistochemistry in tissue samples from more than three hundred individual donors. Stainings were assessed by histopathologic scoring and grouped into high, medium and low expressing subgroups. Results: uPARAP was found to be strongly over-expressed in a high percentage of cases of common STS, with variations in terms of incidence and level of expression between histological subtypes. High uPARAP expression was found in fibro- (86% of cases), synovial (84%), dedifferentiated lipo- (68%), pleomorphic lipo- (65%), myxofibro- (59%), leiomyo- (49%), and myxoid liposarcoma (24%). Work is ongoing in additional sarcoma subtypes. Conclusions: Based on protein expression uPARAP is an attractive emerging therapeutic target for the development of uPARAP-binding ADCs in a broad range of mesenchymal malignancies. In addition, expression of uPARAP in STS may serve as a potential marker for patient selection in early clinical studies with uPARAP-targeting ADCs. Citation Format: Pernille Barkholt, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg, Patrick Schöffski. The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1547.
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Han, Jing, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng i in. "Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models". Cancer Research 83, nr 7_Supplement (4.04.2023): 4017. http://dx.doi.org/10.1158/1538-7445.am2023-4017.
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Abstract Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; >50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations. Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4017.