bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 985: SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPβ/Wnt axis
Authors: Zhang Wenwen , Jiang Mengmeng , Zhang Rui , Liu Pengpeng , Ye Yingnan , Ren Xiubao , Yu Wenwen , Yu Jinpu 
Published: September 2020

Abstract
Early-stage myeloid-derived suppressor cells (eMDSCs) are a newly defined subset of myeloid-derived suppressor cells (MDSCs) that accumulate densely in tumors and potently promote tumor growth and metastasis by suppressing antitumor immune responses in vitro and in vivo. We previously identified a subset of eMDSCs in human breast cancer with a characteristic phenotype of Lin-HLA-DR-CD33+. We also found that SOCS3 deficiency and sustained activation of the JAK/STAT signaling pathway are critical molecular events coordinating the differentiation of eMDSCs, although the distinct molecular regulation has not been fully elucidated. Herein, we genetically constructed conditional SOCS3 knockout mice with SOCS3 deficiency specifically in the myeloid linage (SOCS3MyeKO). We delineated that the number of eMDSCs in SOCS3MyeKO mice (eMDSCsSOCS3KO) with the murine GMP phenotype increased significantly, and these cells suffered from a differentiation block in the myeloid lineage. To explore which pathways participated in dysfunctional eMDSC differentiation, we performed whole-genome RNA sequencing and miRNA microarray on CD11b+Gr-1+ cells, eMDSCsfl/fl and eMDSCsSOCS3KO to screen the potential regulatory ceRNA network in eMDSCsSOCS3KO. CD11b+Gr-1+ cells isolated from SOCS3fl/fl mouse spleens were used as mature myeloid cell controls. The transcriptome results and corresponding intervention experiment revealed that the differentiation block in eMDSCsSOCS3KO was caused by SOCS3 deficiency-mediated limited autophagy activation in an AMPK-independent manner. The results of miRNA microarray and RNA sequencing demonstrated that miR-155 overexpression and Wnt/β-catenin pathway activation were involved in the SOCS3 knockout-mediated myeloid differentiation block and autophagy repression. Further experiments revealed that miR-155 was induced by activation of the STAT3/NK-κB pathway upon SOCS3 deficiency, which consequently activated the Wnt/β-catenin pathway via targeting C/EBPβ. Furthermore, applying a specific miR-155 antagonist or the autophagy agonist rapamycin efficiently suppressed tumor growth and eMDSC infiltration in vivo. Overall, these findings indicated that SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of e-MDSCs via the miR-155/C/EBPβ/Wnt axis, and thus targeted therapy against this pathway could be a potential therapeutic target in breast cancer.
Citation Format: Wenwen Zhang, Mengmeng Jiang, Rui Zhang, Pengpeng Liu, Yingnan Ye, Xiubao Ren, Wenwen Yu, Jinpu Yu. SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPβ/Wnt axis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 985.
Abstract 994: Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects
Authors: Marchetti Carlo , Tengesdal Isak , Dinarello Charles , Fujita Mayumi 
Published: September 2020

Abstract
Introduction: Melanoma NLRP3 inflammasome activation is involved in tumor progression and melanoma-induced immunosuppression via IL-1β-mediated effect.
Abstract: Melanoma-associated inflammation participates in the generation of a tumor permissive environment, which promotes tumor progression and metastasis. The pro-inflammatory cytokine IL-1β mediates several inflammatory diseases and the modulation of the immune system. In the context of malignancy, IL-1β is a validated target in mouse models of cancer, including melanoma, where the cytokine contributes to immunosuppression, angiogenesis, metastasis, and regulation of myeloid derived suppressor cells. In this study, we demonstrate that the NLRP3 inflammasome drives the maturation of the pro-inflammatory cytokine IL-1β in melanoma cells. Accordingly, analysis of melanoma biopsies (N=461) showed increased NLRP3 expression in the lesions which correlates with the IL-1β levels. In melanoma-bearing mice, NLRP3 inhibition with a clinically evaluated NLRP3 inflammasome inhibitor OLT1177 (dapansutrile), showed to decrease melanoma progression and tumor-induced inflammation reducing the circulating levels of IL-6, G-CSF, and VEGF compared to vehicle tumor-bearing mice. Analysis of myeloid-derived suppressor cell (MDSC) populations revealed that NLRP3 inflammasome inhibition was sufficient to prevent MDSCs expansion (both PMN-MDSCs and M-MDSCs), restoring the population to the non-tumor-bearing level. The effect observed on MDSCs in tumor-bearing mice following NLRP3 inhibition resulted in increased NK cells activation in primary tumors (Figure). These data establish a new correlation between IL-1β, NLRP3, melanoma-induced immunosuppression and tumor progression. Considering that NLRP3 inhibition resulted in decreased tumor-induced immune evasion as well as an increased tumoricidal immune response, we evaluated the effect of the addition of NLRP3 inhibition to checkpoint inhibition. Tumor bearing mice treated with OLT1177 and anti-PD-1 showed reduced tumor progression compared to the single-agent treatments. In conclusion, NLRP3 inflammasome inhibition was successful in preventing IL-1β processing in melanoma cells and tumor progression. These findings suggest that NLRP3 may represent a potential therapeutic target for melanoma.
Citation Format: Carlo Marchetti, Isak Tengesdal, Charles Dinarello, Mayumi Fujita. Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 994.
Abstract CT022: A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer
Authors: Papadopoulos Nickolas 
Published: September 2020

Abstract
One of the most compelling approaches to reduce cancer-specific morbidity and mortality is earlier detection. Minimally-invasive screening tests, such as liquid biopsies, hold much promise in this regard. However, prospective clinical studies of these new methods are required to ensure that the anticipated benefits outweigh the potential risks. We describe an interim analysis of a study that enrolled 10,006 women 65 to 75 years of age who had no prior history of cancer, in a population with a high degree of compliance with standard-of-care screening. Enrollment occurred between September 2017 and May 2019. The study evaluated the prospective implementation of a multi-cancer, multi-analyte screening blood test (DETECT-A blood test) incorporating DNA and protein markers. Participants with positive DETECT-A blood test results were followed by an imaging test (generally PET-CT) to localize the putative cancer. The DETECT-A blood test combined with standard-of-care screening doubled the number of cancers detected by screening. The DETECT-A blood test effectively identified subjects with multiple types of cancer, with a positive predictive value higher than existing non-invasive screening tests for individual cancers. The DETECT-A blood test identified ten different cancer types, including seven types for which there is currently no screening test available. No serious adverse events were observed in any participants enrolled in the study. 65% of the cancers detected by the blood test were classified as local or regional disease. Somatic mutations in TP53, BRAF, KRAS, or PIK3CA were the most common alterations identified in plasma; in all cases where tumor tissue was available, the mutations detected in plasma were confirmed to be present in the primary tumor. These results are the first to demonstrate that a minimally-invasive multi-cancer blood test can be safely incorporated into routine clinical care. Moreover, this is the first study to show that it can be used to guide patient management in real-time, leading to surgery with intent to cure in asymptomatic individuals.
Citation Format: Nickolas Papadopoulos. A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT022.
Abstract CT184: Optimizing Tumor Treating Fields therapy for recurrent glioblastoma with targeted and individualized skull remodeling surgery. A multi-center randomized phase 2 trial
Authors: Mikic Nikola , Korshøj Anders R. 
Published: September 2020

Abstract
Background: We will initiate (March 2020) a randomized, comparative, multi-center, investigator-initiated, interventional, phase 2 trial (NCT04223999) testing the efficacy of a potentially new treatment modality for recurrent glioblastoma (GBM). The new treatment modality combines individualized targeted skull remodeling surgery (SR-surgery) with Tumor Treating Fields (TTFields) and best practice medical oncological therapy. The aim of SR-surgery is to enhance the electric field in the tumor region, by removing bone with burrholes. Preclinical research indicate that this modality provides a marked and focal enhancement (~100%) of TTFields. We concluded (April 2019) a phase 1 safety/feasibility trial indicating improved overall survival without additional toxicity from the intervention. The following randomized, comparative phase 2 trial aims to validate superior efficacy of the intervention.
Method: The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields, best practice oncological treatment (control arm) or b) SR-surgery, TTFields and best practice oncology (interventional arm).Major eligibility criteria include age ≥ 18 years, supratentorial GBM, Karnofsky performance score (KPS) ≥ 70, focal tumor, and lack of uncontrollable epilepsy or significant co-morbidity. Study design aims to detect a 20% increase in the overall survival rate 12 months (OS12) assuming OS12 = 40% in the control group and OS12= 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective response rate, quality of life, KPS, steroid dose, and toxicity. Patient follow-up is until death or 36 months (trial duration). Expected average for follow-up is 18 months. Every 3. month there will be an assessment of toxicity, response and QoL. Endpoint data will be collected at the end of the trial, occurrence of suspected unexpected serious adverse reactions (SUSARs) or unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up.
Citation Format: Nikola Mikic, Anders R. Korshøj. Optimizing Tumor Treating Fields therapy for recurrent glioblastoma with targeted and individualized skull remodeling surgery. A multi-center randomized phase 2 trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT184.
Abstract CT262: Multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in HR-positive, HER2-positive metastatic breast cancer
Authors: Cascetta Krystal Pauline , Poulikakos Poulikos , Shapiro Charles , Fasano Julie , Bhardwaj Aarti , Irie Hanna , Goel Anupama , Klein Paula , Ru Meng , Tiersten Amy 
Published: September 2020

Abstract
Background: Overexpression or amplification of HER2 occurs in approximately 15-20% of patients and roughly half of these tumors are hormone receptor (HR) positive. The use of aromatase inhibitors in the metastatic setting is well established while significant improvement in overall survival has been established with the use of trastuzumab or pertuzumab in HER2-overexpressing tumors. This study will examine the combination of endocrine therapy, palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in women with metastatic HR+, HER2+ breast cancer. Trial Design: Multicenter, phase I/II trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR+, Her2+ metastatic breast cancer. Eligibility Criteria: Newly diagnosed stage IV HR+, HER2+ breast cancer patients. Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclib including expression of cyclin D1, cyclin E1 and E2, CDK 2, CDK 4, CDK 6, retinoblastoma, phosphorylated retinoblastoma, and p16. RNA sequencing will be used to assess for other predictors of response in an unbiased manner to assess for correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance. Methods: This study will evaluate the maximum tolerated dose (MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. Once the MTD is reached, we will assess the clinical benefit rate using a Simon's II stage design among a maximum 30 patients. Accrual: Maximum of 36 subjects. Current Enrollment: Enrollment to phase I ended in October 2018 with one dose escalation to palbociclib 125mg, at which level one DLT was observed. Thus, the MTD was determined at palbociclib 125 mg and subsequent phase II patients will be treated at this dose level. Enrollment to phase II began in February 2019. 39% of planned patients have been enrolled as of January 2020. Clinical trial registry number: NCT03304080.
Citation Format: Krystal Pauline Cascetta, Poulikos Poulikakos, Charles Shapiro, Julie Fasano, Aarti Bhardwaj, Hanna Irie, Anupama Goel, Paula Klein, Meng Ru, Amy Tiersten. Multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab in HR-positive, HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT262.
Abstract CT401: The experience of treating patients with cancer during the COVID-19 pandemic in China
Authors: Zhang Li , Zhu F , Xie L , Wang C , Wang J , Chen R , Jia P , Guan H Q. , Peng L , Peng P , Zhang P , Chu Q , Shen Q , Wang Y , Xu S Y. , Zhao J P. , Zhou M , Chen Y 
Published: September 2020

Abstract
Background: Cancer patients are regarded as highly vulnerable group in the current SARS-CoV-2/COVID-19 pandemic. Up to date, the clinical characteristics of cancer patients with COVID-19 are largely unknown.
Patients and methods: In this retrospective cohort study, we collected and analyzed data of the cancer patients with y confirmed COVID-19 infection from three designated hospitals in Wuhan, China from Jan 13, 2020, to Feb 26, 2020. Univariate and multivariate analyses were performed to assess the risk factors associated with severe events defined as a condition that admission to an intensive care unit, the use of mechanical ventilation, or death. We also followed 124 cancer patients with immune checkpoint inhibitors (ICI) and their families for their infection rate and clinical outcome.
Results: Twenty-eight COVID-19 infected cancer patients were included with median age of 65.0 years (IQR:56.0-70.0) and male gender of 60.7% (17/28). Amount of these 28 patients, 7 (25%) had lung cancer, and 8 (28.6%) were considered to be infected via hospital-associated transmission. Fifteen (53.6%) patients had severe events with the mortality rate of 28.6%. The last anti-tumor treatment within 14 days from the diagnoses of COVID significant increased risk of developing severe events (HR=4.079, 95%CI 1.086-15.322, P=0.037). The common chest CT findings were ground-glass opacity (21, 75.0%) and patchy consolidation (13, 46.3%). The patchy consolidation on CT had a higher risk for developing severe events (HR=5.438, 95%CI 1.498-19.748, P=0.010). There was only one patient (1/124, 0.8%) who have been on ICI treatment for his metastatic HCC confirmed with COVID infection, and with mild clinic presentation and a short hospital course.
Conclusions: Cancer patients showed aggressive presentation and poor outcomes with the COVID-19 infection. It is recommended that vigorous screening for COVID-19 infection should be performed for cancer patients with anti-tumor. From our limited data, there is no evidence to suggest difference in cancer patients on ICI treatment.
Citation Format: Li Zhang, F Zhu, L Xie, C Wang, J Wang, R Chen, P Jia, H Q. Guan, L Peng, P Peng, P Zhang, Q Chu, Q Shen, Y Wang, S Y. Xu, J P. Zhao, M Zhou, Y Chen. The experience of treating patients with cancer during the COVID-19 pandemic in China [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT401.
Abstract CT404: Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain
Authors: Gomez-Martin Carlos 
Published: September 2020

Abstract
Since December 2019, when the first cases of pneumonia associated with a new coronavirus were reported in Wuhan (China), we have witnessed the rapid and massive spread of this disease; affecting more than 2 million people worldwide in mid-April. Cancer patients, especially those undergoing active chemotherapy, are especially vulnerable due to treatment-induced immunosuppression and their frequent comorbidities. Despite an increasing number of papers describing the characteristics of the disease and its possible treatments, oncology patients barely represent a minority in the series reported so far, and their peculiar characteristics are not detailed in these publications.
On March 6, 2020, when officially in Spain there were only 117 cases and 2 deceased from COVID19, a patient admitted for another reason was diagnosed with Sars-CoV-2 related infection In the following 48 hours, a full set of new procedures were put in place that modified all the clinical care of our oncology patients.
Regarding Day Hospital and Outpatient clinics on-site active screening by trained staff for all patients and companions were implemented. Also we limited the number of outpatient visits to minimum indispensable. All chemo Treatments were reconsidered based on objectives, life expectancy, and type of therapy and clinical status of every patient.
For all patients admitted routine blood test and Chest Xr or CT of the lungs performed previously to been transferred to Ward. Specifics and separate wards for suspected, confirmed and negative coronavirus patients were prepared as well as dedicated staff (including Oncologist, Infectious Diseases Consultants and Internist) to attend COVID19 + patients 24/7
Since March 9th, more than 280 cancer patients have been actively screened for Sars-coV-2 infection, and 90 patients have been admitted to be specifically treated for this disease.
Data on clinical characteristics and outcomes for the first 63 patients will be presented, with special mention to tumor burden, grade of immunosuppression, type of treatment and comorbidities. Preliminary data on Tocilizumab treatment on this setting will also be shared as well as some significant relationships between clinical and analytical parameters and risk of severe pulmonary and vascular events in this population.
Citation Format: Carlos Gomez-Martin. Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT404.
Abstract LB-005: Senescence reprogramming in primary tumors initiates prostate cancer metastases
Authors: Guccini Ilaria , Revandkar Ajinkya , D'Ambrosio Mariantonietta , Colucci Manuel , Pasquini Emiliano , Mosole Simone , Troiani Martina , Alimonti Andrea 
Published: September 2020

Abstract
Recent studies have raised fundamental questions about the possibility that senescence induced either by oncogene activation or chemotherapy, while initially restricting tumorigenesis, may promote cancer metastases at a late stage. This coexisting dichotomy remains unclear due to the lack of evidence on the mechanism by which senescent tumor cells initiate metastases, a fatal and therapeutically challenging hallmark of cancer. Here, we put forward the hypothesis that the genetic make-up of the tumors accounts for the distinct outcomes of senescence in cancer. Using different genetically engineered mouse models we demonstrate that inactivation of Timp1 is capable to switch senescence driven by the loss of PTEN and chemotherapy from a tumor-suppressive into a tumor-promoting response that drives metastases. Of note, depletion of senescent tumor cells by the senolytic compound ABT263 or p53 genetic inactivation significantly impeded metastases formation in Ptenpc-/-; Timp1-/- mice, indicating the involvement of senescence in the metastatic process. Moreover, enhancement of senescence by Docetaxel therapy decreased the proliferation of prostate tumors in Ptenpc-/- mice, whereas it accelerated metastases formation in Ptenpc-/-; Timp1-/- mice. Mechanistically, TIMP1-loss in PTEN-deficient cells reprogrammed the senescent-secretome significantly changing the levels of GDF15, FGF and IGFBP thereby promoting cellular invasion, migration and the up-regulation of a metastases-associated gene signature. In prostate cancer patients, we found that TIMP1 is commonly lost in combination with PTEN in advanced and metastatic prostate tumors and that TIMP1 inactivation is associated with TIMP1 promoter methylation. Altogether, these findings highlight the crucial role of TIMP1 as the gatekeeper that limits the pro-metastatic function of senescent tumor cells, implying that senescence inducing therapies should be administered with caution in patients affected by cancers with TIMP1 inactivation.
Citation Format: Ilaria Guccini, Ajinkya Revandkar, Mariantonietta D'Ambrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Andrea Alimonti. Senescence reprogramming in primary tumors initiates prostate cancer metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-005.