bluuebunny/crossref_metadata_2025_split huggingface dataset:
ODP559 The prognostic role of IL-17A-neutrophils crosstalk in triple-negative breast cancer
Authors: Khalid Freeha , Takagi Kiyoshi , Guestini Fouzia , Miki Yasuhiro , Miyashita Minoru , Hirakawa Hisashi , Ohi Yasuyo , Rai Yoshiaki , Sagara Yasuaki , Suzuki Takashi , Sasano Hironobu 
Published: November 2022

Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is characterized by extensive intratumoral heterogeneity. At this juncture, TNBCs are treated with conventional chemotherapy and have few targeted therapies. Due to the presence of increased tumor-infiltrating lymphocytes and immune-checkpoint molecules, TNBCs are considered highly immunogenic. This provides an opportunity to explore various immunotherapeutic options. The immune cells such as Th17 cells or neutrophils (tumor-associated neutrophils; TANs) can secrete a pro-inflammatory cytokine called IL-17A, which is known to be associated with poor outcomes in several cancers. TANs are related to tumor progression and are influenced by certain chemokines. Meanwhile, IL-17A can also regulate chemokine (C-X-C motif) ligand 1 (CXCL1), which is a strong chemoattractant for TANs and can lead to the growth of tumors in breast cancer. However, the significance of IL-17A and its interaction with TANs and CXCL1 has yet not been clearly understood in TNBC. For this purpose, formalin-fixed paraffin-embedded biopsy tissue specimens of 109 Japanese TNBC patients were included in this study. Immunohistochemistry was performed to assess the status of IL-17A, CXCL1, and CD66b (a neutrophil marker) and to understand their correlation among each other, with clinical parameters, and with the outcomes of patients. Also, in vitro studies were performed to evaluate the effect of recombinant IL-17A on TNBC cell lines proliferation, migration, and CXCL1 expression. Clinical results revealed that IL-17A was significantly correlated with CXCL1 and CD66b, which suggested potential crosstalk between them. On the other hand, CXCL1 significantly and CD66b tended to be correlated with tumor size. Also, CD66b was significantly correlated with the Ki-67 labeling index, showing that TANs may have a role in tumor cell proliferation. Kaplan-Meier survival curves showed that high IL-17A was significantly associated with poor disease-free and overall survival, indicating the poor outcome of the TNBC patients. To our great interest, in vitro results revealed that no difference was observed for proliferation or migration of TNBC cell lines (was only observed in the MDA-MB-231 cell line) after treatment with recombinant IL-17A. However, CXCL1 was highly up-regulated in a dose and time-dependent manner after exposure to IL-17A, indicating that IL-17A might be involved in the recruitment of neutrophils through up-regulation of CXCL1. Therefore, we concluded that IL-17A was a poor prognostic factor for TNBC patients, enhancing the chemokine-neutrophil recruitment to the tumor site, leading to tumor progression and aggression. In the future, we intend to explore different pathways for understanding the mechanism of CXCL1 up-regulation by IL-17A.
Presentation: No date and time listed
ODP635 A rare case of metastatic papillary thyroid carcinoma on NTRK inhibitor with thyrotoxicosis
Authors: Fazeli Sasan , Zhao Diana 
Published: November 2022

Abstract
We present a case of 26-year-old Hispanic female with neck enlargement and worsening dyspnea. She was noted to have enlarged thyroid nodules; biopsy revealed papillary thyroid carcinoma (PTC) with ETV6-NTRK fusion by next-generation sequencing (NGS). Further work up revealed extensive bilateral milliary pulmonary metastases and Graves’ disease with elevated thyrotropin receptor antibodies and thyroid-stimulating immunoglobulin titers. Tuberculosis work up was negative and bronchoalveolar lavage revealed metastatic PTC. The patient was initiated on larotrectinib (100mg administered twice daily) as well as block-and-replace regimen with levothyroxine and methimazole. Her dyspnea improved and she successfully underwent total thyroidectomy as well as bilateral neck dissections; methimazole and thyroid hormones were discontinued thereafter. Interestingly, patient developed thyrotoxicosis post-surgery even without being on levothyroxine with elevated free T3 at 18 pg/mL (normal range 2.3–4.2), compared to 5.8 pg/mL prior to surgery. Despite discontinuation of levothyroxine, patient continued to be biochemically and clinically hyperthyroid. She was treated with methimazole for 4 months after surgery, and subsequently underwent radioactive iodine (RAI) ablation with 30 mCi of I-131 of sodium iodide. After RAI, thyroid function started to improve, prompting re-initiation of very low dose levothyroxine about 5 months after surgery. Since then, she has remained clinically stable.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
OR30-2 Targeting Succinate Metabolism in Endocrine Therapy Resistant, ER Positive, Breast Cancer Cells
Authors: Andrade de Oliveira Karla , Clarke Robert , Jin Lu , Sengupta Surojeet 
Published: November 2022

Abstract
Estrogen receptor positive (ER+) breast cancer is the most common subtype among all breast cancers and is responsible for most breast cancer related deaths. Endocrine therapies, such as selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI), often given in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, are initially effective but the majority of advanced ER+ breast cancers eventually become refractory to endocrine therapies. Therefore, understanding the underlying molecular mechanisms that enable or promote resistance to endocrine therapies may lead to novel therapeutic targets.Cancer cells have a high energy demand and as a result consume greater quantities of glucose to meet their energy and anabolic demands to support cell growth and proliferation. In this study, we used breast cancer cell models that are endocrine therapy sensitive and resistant and investigated the metabolic flux of glucose by growing the cells in the presence of the stable glucose isotope, UC13-Glucose. We measured the C13-labelled metabolites of glycolysis and the TCA cycle. Glucose consumption was higher in endocrine therapy resistant MCF7/LCC9 (LCC9) cells compared with parental MCF7 (MCF7) and estrogen independent, endocrine therapy sensitive MCF7/LCC1 (LCC1) cells. Notably, in LCC9 cells the m+4 and m+6 isotopomer of C-13 labelled citrate was absent. Further, in LCC9 cells, C-13 labelled fumarate was very low while the succinate: fumarate ratio was markedly higher. These results suggest that the TCA cycle is impaired in LCC9 cells and the conversion of succinate to fumarate is dysregulated. Succinate dehydrogenase (SDH) enzyme is responsible for catalytic conversion of succinate to fumarate. SDH is a multimeric protein comprised of four different subunits and SDH assembly factor 2 (SDHAF2), which is a tumor suppressor gene. Our study further showed that SDHAF2 protein was under expressed in LCC9 cells compared with LCC1 cells, likely contributing to lower SDH activity. Intriguingly, when SDH activity was inhibited using dimethylmalonate, the LCC9 were re-sensitized to both Fulvestrant and 4-hydroxytamoxifen. Data analysis of clinical samples shows that poor relapse free survival in ER+ breast cancer patients is correlated with lower expression levels of SDHAF2. Overall, this study suggests that targeting succinate metabolism may help to restore sensitivity to Fulvestrant and tamoxifen in endocrine therapy resistance in ER+ breast cancer cells.
Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m.
RF05 | PSUN354 Associations between immune-related thyroid dysfunction and efficacy of immune checkpoint inhibitors – A systematic review and meta-analysis
Authors: Cheung Yee-Ming Melody , Wang Wei , McGregor Bradley , Hamnvik Ole-Petter 
Published: November 2022

Abstract

Background
There is growing evidence suggesting that the occurrence of immune-related adverse events (irAEs) may be a predictor of immune checkpoint inhibitor (ICI) efficacy. Whether this association extends to all irAEs or just those within particular organs/systems is yet to be resolved. As immune-related thyroid dysfunction (thyroid irAE) is one of the most commonly reported irAEs, this study aims to summarize the available data and determine if thyroid irAE is a surrogate marker for improved cancer outcomes during ICI therapy.

Methods
PubMed, EMBASE and Cochrane Library were searched up to July 1st 2021 for studies assessing the relationship between thyroid irAE development during ICI therapy and cancer outcomes. Outcome measures of interest include overall survival (OS) and progression free survival (PFS). Sub-group analyses based on cancer type and adjustment for immortal time bias (ITB) were also performed.

Results
Forty-seven studies were included in the systematic review. Twenty-one studies were included in the OS meta-analysis whilst 15 were included in the PFS meta-analysis. Development of thyroid irAE during ICI therapy was associated with improved OS and PFS (OS: HR 0.52, CI 0.43-0.62, p&lt;0.001; PFS: HR 0.58, CI 0.50-0.67, p&lt;0.001). Sub-group analyses involving non-small cell lung cancer populations and studies where ITB was accounted for, observed similar results (HR 0.37, CI 0.24-0.57, p&lt;0.001) and (HR 0.51, CI 0.39-0.69, p&lt;0.001), respectively.

Conclusion
Despite the heterogeneity and biases identified, the evidence does suggest that the development of thyroid irAE is associated with anti-tumor effects of ICIs and therefore, can be used as a surrogate marker for clinical response.
Presentation: No date and time listed
RF07 | PSAT233 The First Case Report of a de-novo Purely Prostatic Large Cell Neuroendocrine Carcinoma with Thyroid and Adrenal Metastases
Authors: Paparodis Rodis , Karvounis Evangelos , Zoupas Ioannis , Bantouna Dimitra , Efthymiadou Roxani , Ioakeimidou Christina , Kelgiorgou Dionysia , Panopoulos Christos 
Published: November 2022

Abstract

Background
Large Cell Neuroendocrine Carcinoma (LCNEC) is the rarest neuroendocrine prostatic malignancy. It usually arises after androgen-deprivation therapy (ADT), while de novo cases are even more infrequent with only 6 cases described to date.

Case presentation
A 78-year-old man with no history of ADT presented with cervical lymphadenopathy. Diagnostic approach included PET/CT, MRI, and CT scans, U/S, biopsies, cytological and immunohistochemical evaluations. CT revealed a non-enriching region on the right lobe of the thyroid gland. An 18F-FDG PET-CT found increased uptake in the thyroid gland and both adrenal glands. Neck ultrasound identified a right thyroid lobe nodule. A fine needle aspiration of the nodule was performed and cytology was consistent with poorly differentiated carcinoma. A total thyroidectomy with central and bilateral lymph node dissection was performed and the pathology report diagnosed a LCNEC metastatic to the thyroid gland. Additional metastases were identified in both adrenal glands. Despite appropriate treatment, the patient succumbed to his disease.

Summary
We report the first patient with a de novo purely prostatic LCNEC, metastasizing to the thyroid and the adrenal glands.

Conclusions
De novo LCNECs of the prostate are very rare, highly aggressive tumors with poor prognosis. They are resistant to most therapeutic agents, have high metastatic potential and are usually diagnosed at an advanced stage. Further studies are needed to characterize these tumors.
Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m.
RF07 | PSUN356 Synergistic Combination of HSP90 and PI3K inhibitors in Adrenocortical Cancer
Authors: Mishra Prachi , Shen Min , Hall Matthew , Zhang Ya-Qin , Nilubol Naris 
Published: November 2022

Abstract
Adrenocortical cancer (ACC) is a rare and aggressive cancer (0.5-2 cases/ million/ year) with a poor 5-year survival (&lt;40%). Most patients inevitably succumb to the wide-spread metastasis because of the lack of effective systemic treatment options or to complications from uncontrolled hypercortisolism. Therefore, it is critically important to identify new effective treatments that can be readily used in a clinical trial. In this direction, we identified a potent synergistic combination of Heat Shock Protein 90 (HSP90) and PI3K inhibitors via quantitative high-throughput drug screening (qHTS) for ACC, using a pharmaceutical library comprised of ∼5000 drugs (FDA approved or investigational), and evaluation of drug synergy by a computerized drug combination matrix analysis. The synergistic efficacy of HSP90 inhibitor STA9090 and PI3K inhibitor, PIK75 was validated in vitro, in ACC cell lines H295R and SW13, by proliferation assay, which also determined the most efficacious doses of individual and combinatorial drugs. The drug combination significantly induced apoptosis and disintegrated the 3D-ACC spheroids as compared to the individual drugs, with a simultaneous upregulation of apoptotic protein markers (cleaved-Caspase3, cleaved-PARP), inhibition of the phosphorylation of PI3K pathway members (AKT1, mTOR, S6K, 4EB1 and GSK3α/β), and alteration in the G2/M phase of the cell cycle, in ACC cells. The synergetic effect of the drug combination was also effective in reducing the metastatic potential as revealed by invasion/migration assay, which was confirmed by the downregulation of the mesenchymal protein (Vimentin, N-cadherin, SNAIL and Zeb1) markers. Consistent with our data, observations from the gene expression data from The Cancer Genome Analysis (TCGA) & Gene Expression Omnibus (GEO) databases, revealed significant mRNA overexpression of HSP90AA1, HSP90AB1 HSP90B1 and its clients AKT2, CDK1, CDK4, NR3C1 indicating both HSP90 and PI3K/AKT pathways are highly activated in ACC cohorts. Overexpression and a positive correlation of mesenchymal markers TWIST1, ZEB1, VIM with HSP90AB1 and PI3KCA, in GEO and TCGA respectively, was consistent with the invasive potential of the ACC cells. In conclusion, our studies on the combination of HSP90 and PI3K inhibitors demonstrated a promising preliminary synergistic efficacy by inhibiting proliferation and epithelial-to-mesenchymal transition of ACC. Our findings can lead to development of an efficient mechanism-specific novel combination therapy that can be expedited to clinical trial in advanced ACC patients.
Presentation: Saturday, June 11, 2022 1:12 p.m. - 1:17 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF19 | PSUN353 Liquid Biopsies - Detecting and Tracking Circulating Cell Free Tumor Derived DNA in Patients with Neuroendocrine Neoplasms
Authors: Gohil Shailesh , Page Karen , Rob Hastings , Iwuji Chinenye , Richards Cathy , Reddy Narendra , Shaw Jacqui , Levy Miles 
Published: November 2022

Abstract

Introduction
There is a clinical need to develop novel and better biomarkers to monitor patients with neuroendocrine neoplasms (NENs). Circulating cell free tumor derived DNA (ctDNA), a form of liquid biopsy, is finding clinical utility in an ever increasing number of malignancies however has not been widely tested in patients with NENs.

Aims
Our aim was to identify and track plasma ctDNA in a cohort of patients with NENs using a personalized, patient specific approach.

Materials and methods
A total of 35 serial plasma samples were collected from 9 patients with metastatic, well differentiated NENs (6 small intestinal and 1 lung, 1 ovarian and 1 pelvic; range 2-5 plasma samples per patient) over the space of 2-25 months. For each patient, NEN specific somatic mutations (single nucleotide variants and insertions/deletions) were identified through whole exome sequencing of paired tumor-leucocyte DNA and were used to design a bespoke multi-variant Ampliseq™ HD ctDNA panel (5-20 variants per patient) for targeted next generation sequencing. Imaging and treatment were provided as per usual clinical care.

Results
ctDNA was detectable in 6/9 patients and in 19/35 plasma samples. A rise in the number of ctDNA target variants and/or variant allele frequency was seen in 4/6 patients who experienced disease progression. Two of these patients received peptide receptor radionuclide therapy after which ctDNA disappeared in one patient and substantially reduced in the other, which correlated with treatment response. The 3 patients who did not have detectable ctDNA at any time point all had grade 1 small intestinal NENs with stable disease during the observation period.

Discussion
Our data provide exciting evidence for the feasibility of using ctDNA as a biomarker in NENs. By targeting multiple individualized variants using next generation sequencing, we have demonstrated that ctDNA can track changes in disease burden and can monitor response to treatment in patients. Of equal importance, ctDNA was not detectable in patients with quiescent disease. This could help identify patients who do not need intensive monitoring. Targeting bespoke, multiple variants per patient is a novel and powerful approach for NENs, especially given their heterogenous genetic landscape. This study provides important early evidence that ctDNA may be a clinically useful biomarker for detection and surveillance of NENs.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m.
RF19 | PSUN383 Potential Role of Activin A During Pancreatic Acinar-to-Ductal Metaplasia of Orthotopic Pancreatic Tumor Mice
Authors: Elesh Ibrahim F , Kim So-Youn , Luan Yi , Oupicky David , Tang Siyuan , Yu Seok-Yeong 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) comprises more than 90% of pancreatic cancer cases and commonly harbors mutations in KRAS and TP53. PDAC is the third leading cause of cancer-related deaths in the US with approximately 10% 5-year relative survival rate. The poor survival rate largely pertains to aggressive growth following metastasis and limited understanding of prognostic factors. Accumulated evidence indicates that PDAC survival rates are inversely correlated with the pancreatic gene expression of INHBA, which encodes inhibin βA, and circulating levels of activin A (a dimer of inhibin βA), which is overexpressed in pancreatic cancer cells. However, potential mechanisms supporting the correlations have remained unclear. PDAC is etiologically related to sustained metaplasia of acinar cells to ductal-like cells (ADM). Therefore, in this study, we tested the hypothesis that activin A plays a tumor-promoting role via ADM. We implanted mouse PDAC KPC (KrasG12D and Tp53R172H) cells into the pancreata of C57BL/6 male mice and divided them into four groups; sham and three groups of orthotopic mice intraperitoneally (IP) injected with either no (TO), scramble (sc) or inhba siRNA (inhba) packaged with CPX nanoparticles, which previously exhibited tumor-targeted delivery, starting on postoperative day 4. On day 16, blood and tissues were harvested for analyses of tumor-related prognostic blood markers and tumor histology. Implanted KPC cells significantly elevated serum activin A levels and induced tumors as demonstrated by the accumulation of SOX9-positive ADM and a-SMA-positive fibroblasts when compared to sham group. Also, metastases occurred to the liver, spleen, kidney, and intestine. No differences were observed between TO and sc groups. However, when compared to sc group, inhba group had significantly suppressed serum activin A levels and reduced tumor size. Statistically, inhba group had fewer metastases and longer survival rates. Histologically, inhba group exhibited more amylase-positive acini conserved and less accumulation of a-SMA-positive cells in the pancreas. Further, the expression of activin A receptor type 2B (ACVR2B) was greatly induced on the acinar cells undergoing ADM transition in sc group, whereas such expression was subdued in inhba group. Collectively, our data indicate that inhba suppression impedes ADM mediated by KPC cells in mice and suggests activin A as one of tumor-initiating factors. It warrants further investigations in human PDAC models and clinical settings to test the potential therapeutic roles of targeting tumor INHBA in early PDAC development.
Presentation: Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
RF27 | LBSUN342 Ar-targeted Linked-read Sequencing Reveals Complex Ar Structural Variants In Castration Resistant Prostate Cancer Models
Authors: Zivanovic Andrej , Munro Sarah A , Miller Jeffrey T , Li Yingming , Passow Courtney N , Dehm Scott 
Published: November 2022

Abstract
Androgen deprivation therapies are employed for the treatment of advanced prostate cancer to suppress the transcriptional activity of the androgen receptor (AR). However, over the course of therapy, AR transcriptional activity re-emerges, and the disease progresses to castration resistant prostate cancer (CRPC). During CRPC progression, AR becomes heavily altered by genomic aberrations that include amplification, missense mutations, and structural variants (SVs). AR SVs are heterogeneous across CRPC specimens, with variability noted in SV class, breakpoint locations, and co-occurrence with amplification. Further variability has been observed for sub-clonal enrichment of AR SVs within tumors. A barrier to understanding the clinical significance of AR SVs is the challenge of deciphering this high degree of variability from short-read DNA-sequencing data. To address this challenge, we performed AR-targeted linked-read DNA-sequencing of CRPC cell line and patient-derived xenograft (PDX) models with the goal of resolving sub-clonal and complex AR SVs. We benchmarked this approach using prostate cancer cell lines and LuCaP86.2 PDX tissue harboring known AR SVs. Using this benchmarking approach, we identified linked AR SVs that co-occurred on single DNA molecules in LuCaP35CR and LuCaP105CR PDX models. We also identified a novel AR SV in the LuCaP77 PDX model and a castration-resistant derivative, LuCaP77CR. These results have revealed heterogeneous trajectories of AR SVs in CRPC and define a new class of complex AR SVs where multiple rearrangements co-occur on single DNA molecules to yield highly rearranged AR gene structures.
Presentation: Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.