bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PO008: ARID1A prevents H3K27-hyperacetylation at active super-enhancers
Authors: Reske Jake J. , Wilson Mike R. , Chandler Ronald L.
Published: February 2021

Mutations in the multi-subunit SWI/SNF (BAF) chromatin remodeling complex are observed in nearly all types of cancer. The most highly mutated subunit across cancer is ARID1A, which occurs in roughly half of uterine endometrial cancer cases. ARID1A mutations and loss of expression are also common in endometriosis. We have previously demonstrated that ARID1A loss drives transcriptional alterations leading to invasive phenotypes through multiple model systems. Yet, how ARID1A regulates transcription through chromatin regulation is poorly understood. We have generated genome-wide profiles of seven chromatin features associated with transcriptional regulation in human endometrial epithelial cells, in both the presence and absence of ARID1A, in order to identify a mechanism by which ARID1A regulates chromatin. Unbiased genome segmentation using these features revealed that ARID1A interacts with chromatin at highly active and accessible enhancers genome-wide. Out of all tested chromatin features, ARID1A most strongly co-localizes with H3K27ac, a mark of transcriptional activation at proximal and distal enhancers. ARID1A depletion also displayed the greatest effect on genomic H3K27ac as opposed to other histone modifications, H3K18ac, H3K4me1, H3K4me3, and H3K27me3. While the majority of typical enhancers had reduced H3K27ac with ARID1A loss, super-enhancers marked by high basal H3K27ac levels displayed hyperacetylation following ARID1A loss. Moreover, increasing H3K27ac was also associated with heightened eRNA transcription, indicating enhancer hyperactivation. Finally, RNA-seq revealed that genes associated with active super-enhancers were preferentially dysregulated following ARID1A loss. These results suggest that ARID1A-SWI/SNF differentially regulate typical enhancers vs. super-enhancers in the endometrial epithelium, and ARID1A may normally restrict super-enhancer hyperactivation to maintain epithelial identity and prevent endometrial invasion.

Citation Format: Jake J. Reske, Mike R. Wilson, Ronald L. Chandler. ARID1A prevents H3K27-hyperacetylation at active super-enhancers [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO008.
Abstract PO022: Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease
Authors: Dvergsten Erik , Karovic Sanja , Thomeas-McEwing Vasiliki , Kimble Danielle , Guo Pingzhen , Yang Hao , Zhao Binsheng , Schwartz Lawrence H. , Maitland Michael L.
Published: February 2021

Evolutionary biology-based methods to characterize human cancer increasingly inform screening, surveillance, and early stage disease treatment strategies. Advanced metastatic disease presents distinct challenges in research and effective treatment. We have established the Advanced Solid Tumor Registry at the Inova Schar Cancer Institute to systematically track quantitative behavior of advanced solid tumors in a “real world” treatment setting. The study supports collection of serial: plasma samples for ctDNA analysis, computed tomography digital images and semi-automated segmentation of lesions for tumor burden volume measurement, and collection of tumor marker measures among patients receiving routine, longitudinal treatment in a community oncology practice. At submission, the study has enrolled 53 patients, 6 with recurrent metastatic endometrial cancer. Study operations have been enhanced by development of R code and workflow to enable graphical display for individual patients in clinically relevant time. In addition to enhancing clinical decision-making for the individual patients, the collective endometrial cancer patient data currently cover 207 patient-months of observation, 119 circulating marker time-points, 73 CT scans, 27 individual lesions, and 20 different courses of treatment. Treatments included palliative radiation, and: cytotoxic, hormonal, immune-, and targeted therapeutics. We propose this registry represents a new tool to support application of evolutionary science-based methods to clinical care and reciprocally to collect “real world” data with sufficient detail to inform computational science assumptions and inferences in multi-scale modeling projects. In this pilot study, individual cases effectively display multiple observations relevant to understanding treatment response in advanced metastatic disease in the clinical care environment. This project was supported, in part, by R01-CA194783.

Citation Format: Erik Dvergsten, Sanja Karovic, Vasiliki Thomeas-McEwing, Danielle Kimble, Pingzhen Guo, Hao Yang, Binsheng Zhao, Lawrence H. Schwartz, Michael L. Maitland. Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO022.
Abstract PO030: Understanding the influence of adiposity on the endometrium using human primary endometrial organoids
Authors: Murphy Alina R. , Kim J. Julie
Published: February 2021

Endometrial cancer is the most commonly diagnosed type of gynecological cancer, and obesity is a major risk factor for this disease. Despite rising rates of obesity and endometrial cancer, it is still unclear how obesity alters the benign endometrium and the endometrial hormonal response to promote carcinogenesis. We used an endometrial organoid model to investigate how adiposity predisposes women to develop endometrial cancer. We hypothesized that increased adiposity would directly alter endometrial gene expression and diminish the protective progesterone response of the benign endometrium. Scaffold-free, three-dimensional endometrial organoids consisting of both epithelial and stromal cells from benign endometrial tissue were generated. Organoids were cocultured with different numbers of adipocyte spheroids to represent different levels of adiposity and were treated with a menstrual cycle level of hormones (E2 + P4 +T) over 14 days. Endometrial organoid gene expression was investigated using RNA-seq. Coculturing endometrial organoids with 30 adipocyte spheroids in the presence of E2, P4, and T caused significant differential expression of pathways involved in metabolism, angiogenesis, chromatin modification, and metal ion response, compared to endometrial organoids cultured without adipocyte spheroids. We investigated the metal ion response pathways that were altered and found that many of the most significantly differentially regulated genes in the metal ion response pathways belonged to the metallothionein (MT) family of genes. The expression of MT1A, MT1M, MT1X, and MT2A decreased approximately 50% in endometrial organoids cocultured with 30 adipocyte spheroids. Furthermore, although the results were not statistically significant, we observed a downregulation of the progesterone-responsive genes HSD17B2, IGFBP1, PAEP, PRL, FOXO1, and SPP1 in the endometrial organoids cultured with 30 adipocyte spheroids. Our results show that culturing endometrial organoids in conditions of increased adiposity alters endometrial gene expression and may change the way the endometrium responds to progesterone. Metallothioneins, which are downregulated in the presence of adipocyte spheroids, are important modulators of zinc and copper ions and reactive oxygen species in the cell. Progesterone plays an important protective role against endometrial cancer. In summary, our data show that adipocytes may influence the progesterone response of the benign endometrium. Further investigation into the role of progesterone-driven metallothioneins in the endometrium is currently underway.

Citation Format: Alina R. Murphy, J. Julie Kim. Understanding the influence of adiposity on the endometrium using human primary endometrial organoids [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO030.
Abstract PO033: FGFR2 isoform switching strongly associates with progestin treatment failure in atypical hyperplasia and well-differentiated endometrial cancer
Authors: Sengal Asmerom , Smith Deborah , Rogers Rebecca , Snell Cameron , Williams Elizabeth , Pollock Pamela
Published: February 2021

Introduction: Women with atypical hyperplasia (AH) or well-differentiated endometrioid endometrial carcinoma (EEC) who wish to retain fertility and/or with severe comorbidities that preclude surgery, are treated with progestin. Previously, we reported FGFR2c was associated with aggressive tumour behaviour and poor survival outcome in EEC. The purpose of this study was to estimate the response rate of Levonorgestrel IUD treatment and determine the association of FGFR2b and FGFR2c expression with outcome in women with AH/borderline histology (BL) and EEC treated with progestin.

Method: BaseScope RNA ISH and immunohistochemistry assays were deployed to detect (FGFR2b and FGFR2c mRNA) and (FGFR2 protein and progesterone receptors), respectively in 89 diagnostic biopsies of patients with AH/BL and EEC treated with progestin. Kaplan Meier Curve and Cox regression model analyses were performed to evaluate the predictive value of FGFR2b and FGFR2c in this cohort.

Results: The complete resolution rate (CRR) and overall response rate (ORR) at any time point in the whole cohort were 26/82 (32%) and 35/82 (43%), respectively. When stratified by histologic diagnosis CRR was 47.5% and 17% and ORR 63% and 24% for AH/BL and EEC, respectively. The recurrence rate was 28.7%. FGFR2c expression was documented in 12/72 (15%) cases. Both univariable and multivariable Cox regression analyses showed women with FGFR2c expression were 5-fold more likely to progress compared with FGFR2b positive women (HR 5.4, P<0.0001) and (HR, 5, P<0.001), respectively.

Conclusion: Progestin treatment is less effective in patients with EEC. Notably, FGFR2c expression appears to be strongly associated with progestin treatment failure.

Citation Format: Asmerom Sengal, Deborah Smith, Rebecca Rogers, Cameron Snell, Elizabeth Williams, Pamela Pollock. FGFR2 isoform switching strongly associates with progestin treatment failure in atypical hyperplasia and well-differentiated endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO033.
Abstract PO042: ROR2 is epigenetically regulated in endometrial cancer
Authors: Liu Dongli , Enriquez Luis , Daniels Benjamin , O'Mara Tracy , Tang Katrina , Ford Caroline
Published: February 2021

BACKGROUND: The Wnt signalling receptor ROR2 has been identified as a potential target in numerous cancers, however its exact role remains controversial. ROR2 has been shown to play distinct roles in regards to tumorigenesis in different tumour types. Our previous study suggested a potential tumour suppressor role for ROR2 in endometrial cancer (EC), however the mechanism associated with ROR2 repression in EC remains unclear. ROR2 has been found to be epigenetically inactivated in colorectal cancer. OBJECTIVE: The aim of this study was to investigate the role of ROR2 in EC, and to determine if ROR2 expression in EC was regulated epigenetically. METHODS: The correlation between ROR2 mRNA expression levels and clinicopathological parameters, including overall survival (OS) was analysed in The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC, n=546) cohort and GEO datasets (GSE17025, n=91). Immunohistochemistry (IHC) of ROR2 was performed on a large EC patient cohort (Australia-wide population-based Australian EC Study, ANECS, n=499). The correlation between ROR2 staining intensity (0-3) and clinicopathological parameters as well as 5-year progression free survival (PFS) and OS was analysed. Cox regression was also applied to analyse the impact of selected covariates (age, BMI, FIGO stage and grade) on the PFS and OS. Four EC cell lines (KLE, MFE-296, Ishikawa and ARK-1) and eight clinical EC samples were analysed for ROR2 methylation via COmbined Bisulphite Restriction Analysis (COBRA) and bisulphite genomic sequencing (BGS). RESULTS: ROR2 promoter methylation or reduced ROR2 expression were both found to correlate with lower OS, high grade and serous EC in the TCGA-UCEC and GEO dataset at p<0.05 level. In our ANECS cohort, the same trend of correlation was observed of ROR2 expression and grade (p=0.062). No significant correlation was observed for ROR2 expression with OS or PFS in this cohort at univariate or multivariable survival analysis. ROR2 was epigenetically silenced by promoter methylation in KLE and ARK-1 cell lines. There was also a significant correlation between ROR2 expression level and promoter methylation in our patient cohort (r=-0.79, p=0.02). CONCLUSION: ROR2 plays a tumour suppressor role in EC and is epigenetically suppressed with the development of disease. It may therefore be a diagnostic or therapeutic candidate for EC.

Citation Format: Dongli Liu, Luis Enriquez, Benjamin Daniels, Tracy O'Mara, Katrina Tang, Caroline Ford. ROR2 is epigenetically regulated in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO042.
Abstract PO047: AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer
Authors: Toboni Michael D. , Mullen Mary , Tankou Jo'an , Noia Hollie , Oplt Alyssa , Wilke Daniel , Khabele Dineo , Kuroki Lindsay , Hagemann Andrea , McCourt Carolyn , Thaker Premal , Mutch David , Powell Matthew , Fuh Katherine
Published: February 2021

Objectives: We determined whether inhibition of GAS6/AXL with AVB-500 in combination with olaparib could improve response in HR-proficient (HRP) uterine serous cancer (USC). Methods: Two USC cell lines (ARK1 & ARK4) were radiated with 10Gy, and RAD51 foci were identified by immunofluorescence (IF). These were treated with AVB-500 (Aravive Biologics, Houston, TX) in combination with the poly ADP ribose polymerase (PARP) inhibitor, olaparib. Colony forming assays were assessed after 4 days of treatment with either AVB-500 alone, olaparib alone or combination treatment (olaparib + AVB-500). Colonies were stained and absorbance was obtained to calculate relative cell survival using Graph Pad Prism. In vivo studies were performed using NOD-SCID mice injected with 1 × 107 ARK1 cells intraperitoneally followed by treatment q3 days for 14-day treatment period. Treatment groups were vehicle control, AVB-500 alone, olaparib alone and olaparib with AVB-500. Results: ARK1 and ARK4 cells were found to have an increase in gamma-H2AX and RAD51 foci after radiation that was consistent with HRP. In clonogenic assays, colonies were stained and absorbance was obtained for each experimental arm. Olaparib + AVB-500 had significantly less absorbance than the olaparib only group for ARK1s (0.417nm vs 0.756nm, p=0.001) as well as in ARK4s (0.186nm vs 0.641nm, p=0.003). In an intraperitoneal model with ARK1 tumors, the olaparib + AVB-500 treated group had less tumor weight than those treated with olaparib alone (0.008g vs 0.138g, p=0.002) and AVB-500 alone (0.008g vs 0.145g, p=0.0006) after a 14-day treatment period. Conclusions: AVB-500 in combination with olaparib demonstrates an improved response than olaparib alone with a greater decrease in tumor burden. This was demonstrated in two HRP cell lines. Additional therapeutic and mechanistic experiments are ongoing.

Citation Format: Michael D. Toboni, Mary Mullen, Jo'an Tankou, Hollie Noia, Alyssa Oplt, Daniel Wilke, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. AVB-500, a receptor tyrosine kinase AXL inhibitor, improves response to olaparib in uterine serous cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO047.
Abstract PR003: Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility
Authors: O'Mara Tracy A. , Kho Pik Fang , Partida Gabriel Cuellar , Spurdle Amanda B. , Glubb Dylan M.
Published: February 2021

To date, genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic risk regions; however, candidate susceptibility genes at these regions are yet to be confirmed. We performed a transcriptome-wide association study (TWAS) to identify candidate endometrial cancer susceptibility genes and provide evidence to support previously identified candidate genes. To maximise statistical power, we used a multi-tissue TWAS approach, integrating the largest endometrial cancer GWAS (12,906 cases and 108,979 controls of European ancestry) with cis-expression quantitative trait loci (eQTLs) from 48 tissues. Identified genes were prioritised by colocalisation analysis to reduce false positive findings. We found seven candidate endometrial cancer susceptibility genes, six of which had previously been identified as candidate susceptibility genes by parallel functional analyses. The remaining identified gene was a lncRNA located at a potentially novel endometrial cancer genetic risk region. Using phenome-wide association approaches, we found these genes associate with traits related to endometrial cancer risk factors, including cardiovascular phenotypes, diabetes, and hormone levels. This analysis additionally identified associations with traits related to bone health, haematopoiesis and liver function, providing avenues for future study. Comparing genetically predicted endometrial cancer gene expression with drug-induced gene expression profiles from the Connectivity Map database, we identified 14 drug repurposing candidates including tubulin inhibitors, a drug class already in use for treatment of advanced endometrial cancer. In summary, using TWAS we have identified candidate endometrial cancer susceptibility genes and provided evidence to prioritise existing candidates. Follow-up analyses have revealed further potential risk factors for endometrial cancer and compounds that could be repurposed for endometrial cancer treatment.

Citation Format: Tracy A. O'Mara, Pik Fang Kho, Gabriel Cuellar Partida, Amanda B. Spurdle, Dylan M. Glubb. Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR003.
Abstract PR004: Multi-dimensional biomarker analyses identify pembrolizumab responders in advanced stage, high grade endometrial cancer
Authors: Fuh Katherine , Lomonosova Elena , Pachynski Russell , Malkova Olga , Oh Stephen , Hagemann Andrea , McCourt Carolyn , Powell Matthew , Fantl Wendy , Thaker Premal
Published: February 2021

Objectives: The recent FDA approval of pembrolizumab for the treatment of recurrent, tissue agnostic cancers with Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) has led to the treatment of a selected cohort of endometrial cancer (EC) patients. Methods: We designed a study to ascertain tumor immune modulatory effects of pembrolizumab in the front-line setting for advanced stage III/IV surgically-resectable endometrial cancers regardless of MSI-H or dMMR status. The primary objectives were to determine the safety of treatment with pembrolizumab by radiographic imaging and to determine progression-free survival at 6 months. Exploratory objective was to compare the immune response before and after treatment. In an open label, single-arm Phase I trial, 8 EC patients were treated with 2 doses of preoperative pembrolizumab IV prior to surgery followed by carboplatin and paclitaxel and 4 doses of pembrolizumab 200mg/kg q3 weeks IV. Peripheral blood was collected from EC patients at baseline level before treatment and post 2 doses of pembrolizumab treatment. Blood from healthy controls (HC) was also collected. Both were processed for high-dimensional single-cell mass cytometry (CyTOF) using an optimized lymphoid and myeloid panel. Results: Patients who responded to therapy showed lower frequency of circulating CD8+ naïve T cells but higher frequency of CD8+ effector T cells after the treatment than the poor responders. We observed post-therapy expansion of populations of CD8+ and CD4+ T cells expressing co-stimulatory receptor ICOS in responders but not in poor responders. Granzyme+CD8+ and Granzyme+CD4+ T cell populations were expanded after pembrolizumab treatment in responders but were decreased in poor responders. Higher frequency of CD27+Fas- CD4+ T cells at baseline and increased frequency of CD27-Fas+CD4+ T cells post-treatment were observed in responders but not in the poor responders. Furthermore, we identified that circulating MDSCs were reduced after pembrolizumab treatment in responders. Conclusions: Our results suggest that peripheral blood analysis may provide valuable insights into responses to anti-PD-1-targeted therapies in patients with endometrial cancers.

Citation Format: Katherine Fuh, Elena Lomonosova, Russell Pachynski, Olga Malkova, Stephen Oh, Andrea Hagemann, Carolyn McCourt, Matthew Powell, Wendy Fantl, Premal Thaker. Multi-dimensional biomarker analyses identify pembrolizumab responders in advanced stage, high grade endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR004.
Abstract PR007: Genomic characterization of endometrial cancer patient-derived xenografts reveals intratumor heterogeneity
Authors: Kondrashova Olga , Bonazzi Vanessa F. , Smith Deborah , Nones Katia , Sengal Asmerom , Ju Robert , Packer Leisl M. , Koufariotis Lambros T , Kazakoff Stephen H. , Davidson Aimee L. , Ramarao-Milne Priya , Lakis Vanessa , Newell Felicity , Rogers Rebecca , Davies Claire , Chetty Naven , Perrin Lewis , Pearson John , Patch Ann-Marie , Garrett Andrea , Waddell Nicola , Pollock Pamela , Nicklin James
Published: February 2021

Endometrial cancer is a major gynaecological cancer with a high incidence resulting in over 500 Australian women dying every year. Good pre-clinical models are urgently needed to study the biology of this disease, and to develop and test novel treatment strategies. Most current pre-clinical research is conducted in cell lines that often do not resemble the disease on the molecular level and do not recapitulate tumour heterogeneity, which results in untranslatable research findings. Patient-derived xenograft (PDX) models overcome the issues of representing tumour molecular landscape and heterogeneity, making them a translatable pre-clinical cancer model. Here, we generated and genomically characterised 11 PDX models by performing whole genome or whole exome sequencing of primary patient tumours and matched PDX samples. We performed a detailed genomic characterisation of these models to determine their suitability as pre-clinical models, study tumour heterogeneity and identify biomarkers of response and resistance. PDX models were successfully generated from all four molecular subtypes of EC and uterine carcinosarcomas, and they recapitulated morphology and the molecular landscape of primary tumors without major genomic drift. We also observed a wide range of inter-tumor and intra-tumor heterogeneity, well captured by different PDX lineages, which could lead to different treatment responses. An in vivo response to talazoparib was detected in two p53mut models consistent with stable disease, however both lacked the HR deficiency genomic signature. EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the p53mut molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.

Citation Format: Olga Kondrashova, Vanessa F. Bonazzi, Deborah Smith, Katia Nones, Asmerom Sengal, Robert Ju, Leisl M. Packer, Lambros T Koufariotis, Stephen H. Kazakoff, Aimee L. Davidson, Priya Ramarao-Milne, Vanessa Lakis, Felicity Newell, Rebecca Rogers, Claire Davies, Naven Chetty, Lewis Perrin, John Pearson, Ann-Marie Patch, Andrea Garrett, Nicola Waddell, Pamela Pollock, James Nicklin. Genomic characterization of endometrial cancer patient-derived xenografts reveals intratumor heterogeneity [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PR007.
Squamous Cell Carcinoma within a Congenital Nevus Sebaceous: Case Report and Literature Review
Authors: Achavanuntakul Petchlada , Thanomkitti Kanchalit
Published: February 2021

Nevus sebaceous (NS) is a benign hamartoma that typically occurs on the head and neck area at birth. Occasionally, secondary neoplasms can develop on top of the original nevus, which usually occur in the middle age. Squamous cell carcinoma (SCC) arising in NS may occur but is very rare. We report the case of a 44-year-old female with an asymptomatic erythematous papule arising within a hairless yellowish plaque on the left parietal area of her scalp for a month. An excisional biopsy was done, and the histopathologic examination revealed SCC arising in the NS.
Eosinophilic Vulvar Leukoderma
Authors: Nakada Kaya , Niiyama Shiro , Oharaseki Toshiaki , Fukuda Hidetsugu
Published: February 2021

We report the case of a 54-year-old woman with asthma and atopic dermatitis who presented a white spot on the genitalia. Histologic examination showed numerous eosinophils in the epithelium and the dermis. Eosinophilic esophagitis is defined as an esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammation. We discuss the possible relationship between the two diseases.
Dapagliflozin in a Real-World Chronic Heart Failure Population: How Many Are Actually Eligible?
Authors: Maltês Sérgio , Cunha Gonçalo J.L. , Rocha Bruno M.L. , Presume João , Guerreiro Renato , Henriques Célia , Rodrigues Catarina , Araújo Inês , Fonseca Cândida
Published: February 2021

Background: In patients with heart failure (HF) and reduced ejection fraction (HFrEF) with or without type 2 diabetes mellitus, the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin was recently shown to reduce the risk of worsening HF or death from cardiovascular causes in the dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF) trial. Our goal was to investigate how many patients in a real-world setting would be eligible for dapagliflozin according to the DAPA-HF enrolment criteria. Methods: This is a single-center retrospective study enrolling consecutive, unselected patients followed up in an HF clinic from 2013 to 2019. Key DAPA-HF inclusion criteria (i.e., left ventricular ejection fraction [LVEF] ≤40% and NT-proBNP ≥600 pg/mL [or ≥900 pg/mL if atrial fibrillation]) and exclusion criteria (estimated glomerular filtration rate [eGFR] <30 mL/kg/1.73 m2 and systolic blood pressure [SBP] <95 mm Hg) were considered. Results: Overall, 479 patients (age 76 ± 13 years; 50.5% male; 78.9% hypertensive; 45.1% with an eGFR <60 mL/min/1.73 m2; 36.5% with TD2M; and 33.5% with ischaemic HF) were assessed. The median SBP was 128.5 (112.0–146.0) mm Hg, mean eGFR was 50.8 ± 23.7 mL/min/1.73 m2, and median NT-proBNP was 2,183 (IQR 1,010–5,310) pg/mL. Overall, 155 (32.4%) patients had LVEF ≤40%. According to the DAPA-HF trial key criteria, 90 patients (18.8%) would be eligible for dapagliflozin. The remainder would be excluded due to LVEF >40% (67.6%), eGFR <30 mL/min/1.73 m2 (19.4%), NT-proBNP below the cutoff (16.7%), and/or SBP <95 mm Hg (6.5%). If we center the analysis to those with LVEF ≤40%, 58.1% would be eligible for dapagliflozin. The remainder would be excluded due to an eGFR <30 mL/min/1.73 m2 (20%), NT-proBNP below the cutoff (16.1%), and/or SBP <95 mm Hg (8.4%). Conclusion: Roughly half of our real-world HFrEF cohort would be eligible for dapagliflozin according to the key criteria of the DAPA-HF trial. The main reason for non-eligibility was an eGFR <30 mL/min/1.73 m2. However, two-thirds of patients had LVEF >40%. These findings show that dapagliflozin is a promising complementary new drug in the therapeutic armamentarium of most patients with HFrEF, while highlighting the urgent need for disease-modifying drugs in mid-range and preserved LVEF and the need to assess the efficacy and safety of SLGT2i in advanced kidney disease patients. The results of ongoing SGLT2i trials in these LVEF subgroups are eagerly awaited.
Detection of Major Cardioembolic Sources in Real-World Patients with Ischemic Stroke or Transient Ischemic Attack of Undetermined Cause
Authors: van der Maten Gerlinde , Reimer Jorieke M.B. , Meijs Matthijs F.L. , von Birgelen Clemens , Brusse-Keizer Marjolein G.J. , den Hertog Heleen M.
Published: February 2021

Background/Aim: Current guidelines recommend transthoracic echocardiography (TTE) and ambulatory rhythm monitoring following ischemic stroke or transient ischemic attack (TIA) of undetermined cause for identifying cardioembolic sources (CES). Due to ongoing controversies about this routine strategy, we evaluated its yield in a real-world setting. Methods: In a tertiary medical center, we retrospectively evaluated consecutive patients with ischemic stroke or TIA of undetermined cause, who (after standard work-up) underwent TTE, ambulatory rhythm monitoring, or both. CES were classified as major if probably related to ischemic events and warranting a change of therapy. Results: Between January 2014 and December 2017, 674 patients had ischemic stroke or TIA of undetermined cause. Of all 484 patients (71.8%) who underwent TTE, 9 (1.9%) had a major CES. However, 7 of them had already been identified for cardiac evaluation due to new major electrocardiographic abnormalities or cardiac symptoms. Thus, only 2 patients (0.4%) truly benefitted from unselected TTE screening. Ambulatory rhythm monitoring was performed in 411 patients (61.0%) and revealed AF in 10 patients (2.4%). Conclusion: Detecting a major CES is essential because appropriate treatment lowers the risk of recurrent stroke. Nonetheless, in this real-world study that aimed at routine use of TTE and ambulatory rhythm monitoring in patients with ischemic stroke or TIA of undetermined cause, the prevalence of major CES was low. Most patients with major CES on TTE already had an indication for referral to a cardiologist, suggesting that major CES might also have been identified with a much more selective use of TTE.
Cytological Sub-Classification of Atypia of Undetermined Significance May Predict Malignancy Risk in Thyroid Nodules
Authors: Elomami Abdulghani , Elhag Shahad Abobakr , Alseddeeqi Eiman
Published: February 2021

Background: Atypia/follicular lesion of undetermined significance (AUS/FLUS) carries a malignancy risk reaching up to 50%. Based on the reported malignancy rate in a given population, the clinical practice towards such a category varies. We hereby identify clinical parameters for risk stratification to aid in decision-making for either surgical referral or a clinical follow-up. Our aim is to identify clinical parameters that guided both clinicians and patients at our institutions to reach a clinical decision including atypia types. Methods: A retrospective review of patients with Bethesda III category thyroid nodules from tertiary centres in the Emirate of Abu Dhabi during January 2011 through December 2015 was carried out. Malignancy risk in Bethesda category III nodules and repeat FNA utility were calculated. Parameters that guided both clinicians and patients for appropriate referral to surgery were studied. Results: Two hundred and two cases were included in the study. Of these, 101 cases underwent surgery initially following the first FNA and 10 cases following FNA repeat. Histology confirmed malignancy in (41%) of cases that went initially to surgery and in (40%) of cases that underwent a repeat FNA. Repeat FNA resulted in 17 (44.74%) cases being re-classified into benign category, 10 (26.3%) being AUS/FLUS category, 6 (15.7%) being both suspicious and malignant, and 5 (13.16%) being unsatisfactory. Repeating FNA resulted in a definitive diagnostic utility in 50% of the cases. Eighty percent of malignant cases demonstrated nuclear atypia. Conclusion: The relatively high malignancy rate in our institutions, the suspicious radiographic features, the atypia groups, and the repeat FNA predictive value stratified Bethesda III category nodules for proper malignancy prediction and appropriate management.
Validation of Microbiological Testing of Tissue Preparations with Different Incubation Temperatures
Authors: Herrlinger Frithjof , Schulz Tino , Pruß Axel , Schulz Eva
Published: February 2021

Introduction: The European Pharmacopoeia (Ph. Eur.) provides principles for microbiological testing of tissue preparations. According to the Ph. Eur., tests should be performed at different temperatures for detection of aerobic bacteria and fungi (20–25°C) vs. anaerobic bacteria (30–35°C). Semiautomated systems using blood culture bottles are already widely used and they are adequate for growth detection. Resin-containing bottles and the addition of penicillinase permit testing of culture media containing antibiotics. Materials and Methods: At 3 temperatures (21, 30, and 35°C) cornea culture media with and without dextran (CM II and CM I) and thermal disinfected femoral head medium (FH) were spiked with the 6 reference strains recommended by the Ph. Eur. (additionally: Enterococcus faecalis, Staphylococcus epidermidis, and Cutibacterium acnes). Microbial growth was monitored with the BACTECTM FX unit or visually at 21°C. Results: Growth for all strains was detected with each medium at all 3 temperatures, except for C. acnes at 21°C (all media) and 30°C with FH. C. acnes had the highest times to detection, requiring test durations of 14 days. Microbial growth was faster at 30 and 35°C compared to 21°C. Conclusion: The requirements according to the Ph. Eur. for a successful method suitability test could be fulfilled for the semiautomated blood culture bottle system with the BACTECTM FX unit for the media and microorganisms used. In the presented validation study 35°C was shown to be the incubation temperature with the fastest growth, of the majority of the test strains used, and complete detection within 14 days.
Impact of New Grading System and New Hemodynamic Classification on Long-Term Outcome in Patients With Severe Tricuspid Regurgitation
Authors: Omori Taku , Uno Goki , Shimada Shunsuke , Rader Florian , Siegel Robert J. , Shiota Takahiro
Published: February 2021

Background:

A new grading of tricuspid regurgitation (TR) beyond severe has been proposed. However, few studies assessing the validity of such a new grading scheme of TR have been conducted. Therefore, we evaluated associations of TR grades beyond severe with patient outcome and hemodynamics.

Methods:

We retrospectively studied patients who underwent 2-dimensional echocardiography and were diagnosed with severe TR between January 2014 and December 2015. According to the vena contracta width of TR (VC), the patients were classified into 2 groups: VC under 14 mm (VC<14 mm) and VC 14 mm or greater (VC≥14 mm). Hemodynamic parameters were estimated by echocardiography and were obtained by right heart catheterization. Cardiovascular events were defined as cardiovascular death or admission for heart failure.

Results:

A total of 679 patients (mean 72±17 years, 56% women) were included. During follow-up (median, 158 days; range, 29–891), 210 patients experienced cardiovascular events. By multivariate analysis, VC≥14 mm and left ventricular ejection fraction were independent predictors of cardiovascular events (hazard ratio, 1.57 [1.06–2.33]; hazard ratio, 0.99 [0.98–0.99], respectively). Patients with VC≥14 mm had significantly lower cardiac index (median, 1.8 versus 2.1 L/min per m
2
,
P
=0.001) and a higher prevalence of right atrial pressure 15 mm Hg (74% versus 60%,
P
<0.001) on echocardiography. Also, right heart catheterization confirmed higher right atrial pressure in patients with VC≥14 mm than those with VC<14 mm (16±8 versus 12±6 mm Hg,
P
=0.004). The new subset classification developed by cardiac index and right atrial pressure both on echocardiography predicted cardiovascular events (Log-rank
P
<0.001).

Conclusions:

The relationship of VC≥14 mm to adverse outcome and poor hemodynamics showed the clinical relevance and need of a new grading system beyond severe. The new hemodynamic subset classification provides additional prognostic value for cardiovascular events in patients with severe TR.
The 2020 “WHO Technical Specifications for Automated Non-Invasive Blood Pressure Measuring Devices With Cuff”
Authors: John Oommen , Campbell Norm R.C. , Brady Tammy M. , Farrell Margret , Varghese Cherian , Velazquez Berumen Adriana , Velez Ruiz Gaitan Laura A. , Toffelmire Nicola , Ameel Mohammad , Mideksa Mulugeta , Jaffe Marc G. , Schutte Aletta E. , Khan Taskeen , Lopez Meneses Laura Patricia
Published: February 2021

High systolic blood pressure (BP) is the single leading modifiable risk factor for death worldwide. Accurate BP measurement is the cornerstone for screening, diagnosis, and management of hypertension. Inaccurate BP measurement is a leading patient safety challenge. A recent World Health Organization report has outlined the technical specifications for automated noninvasive clinical BP measurement with cuff. The report is applicable to ambulatory, home, and office devices used for clinical purposes. The report recommends that for routine clinical purposes, (1) automated devices be used, (2) an upper arm cuff be used, and (3) that only automated devices that have passed accepted international accuracy standards (eg, the International Organization for Standardization 81060-2; 2018 protocol) be used. Accurate measurement also depends on standardized patient preparation and measurement technique and a quiet, comfortable setting. The World Health Organization report provides steps for governments, manufacturers, health care providers, and their organizations that need to be taken to implement the report recommendations and to ensure accurate BP measurement for clinical purposes. Although, health and scientific organizations have had similar recommendations for many years, the World Health Organization as the leading governmental health organization globally provides a potentially synergistic nongovernment government opportunity to enhance the accuracy of clinical BP assessment.
Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage
Authors: Sprügel Maximilian I. , Kuramatsu Joji B. , Volbers Bastian , Saam Justina I. , Sembill Jochen A. , Gerner Stefan T. , Balk Stefanie , Hamer Hajo M. , Lücking Hannes , Hölter Philip , Nolte Christian H. , Scheitz Jan F. , Rocco Andrea , Endres Matthias , Huttner Hagen B.
Published: February 2021

Background and Purpose:

The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied.

Methods:

Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH.

Results:

A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03–2.40];
P
=0.038). Initiation of statins after ICH was associated with increased peak PHE (β=0.12, SE=0.06,
P
=0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation (
P
>0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80–1.66];
P
=0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09–2.56];
P
=0.019).

Conclusions:

Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.
Association of Plasma Neurofilament Light With Small Vessel Disease Burden in Nondemented Elderly
Authors: Qu Yi , Tan Chen-Chen , Shen Xue-Ning , Li Hong-Qi , Cui Mei , Tan Lan , Dong Qiang , Yu Jin-Tai ,   on behalf of the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2021

Background and Purpose:

Neurofilament light chain (NfL) is a promising predictive biomarker of active axonal injury and neuronal degeneration diseases. We aimed to evaluate if an increase in plasma NfL levels could play a monitoring role in the progression of cerebral small vessel disease (CSVD) among the nondemented elders, which are highly prevalent in elderly individuals and associated with an increased risk of stroke and dementia.

Methods:

The study included 496 nondemented participants from the Alzheimer disease neuroimaging initiative database. All participants underwent plasma NfL measurements and 3.0-Tesla magnetic resonance imaging of the brain; 387 (78.0%) underwent longitudinal measurements. The number of cerebral microbleeds, lacunar infarcts, and volumetric white matter hyperintensities, as well as Fazekas scores, were measured. Cross-sectional and longitudinal associations between CSVD burden and NfL levels were evaluated using multivariable-adjusted models.

Results:

Plasma NfL was higher in the moderate-severe CSVD burden group (45.2±16.0 pg/mL) than in the nonburden group (34.3±15.1 pg/mL; odds ratio [OR]=1.71 [95% CI, 1.24–2.35]) at baseline. NfL was positively associated with the presence of cerebral microbleeds (OR=1.29 [95% CI, 1.01–1.64]), lacunar infarcts (OR=1.43 [95% CI, 1.06–1.93]), and moderate-severe white matter hyperintensities (OR=1.67 [95% CI, 1.24–2.25]). Longitudinally, a higher change rate of NfL could predict more progression of CSVD burden (OR=1.38 [95% CI, 1.08–1.76]), white matter hyperintensities (OR=1.41 [95% CI, 1.10–1.79]), and lacunar infarcts (OR=1.99 [95% CI, 1.42–2.77]).

Conclusions:

Plasma NfL level is a valuable noninvasive biomarker that supplements magnetic resonance imaging scans and possibly reflects the severity of CSVD burden. Furthermore, high plasma NfL levels tend to represent an increased CSVD risk, and dynamic increases in NfL levels might predict a greater progression of CSVD.
Homo Sapiens, Mnesitardigrada Class and Umwelt: A Dialogue on Interspecies Organic Data Flow
Authors: Dementieva Alexandra , Chiri Zandrine
Published: February 2021

This article presents artistic research based on existing knowledge about interspecific communication and hypothesis about the spread of interplanetary civilizations. It is expressed as an imagined communication flow between a human earthling scientist and a Kquaanian–human hybrid who is an artist by earthly occupation. While these two species’ sensoria are too different to allow discussion, this consideration supports the poetic approach to interspecies understanding, through immersive interactive installations and a willingness to share thoughts and feelings, in answering questions about the world and our place in it. The organs, molecules and protein expression of tardigrades provide a point of departure.
Space Art as a Critique of Space Law
Authors: Vermeylen Saskia
Published: February 2021

This article traces the shared history of space law and space art, putting a spotlight on the work of African artists who retell the history and future of space travel from the perspective of the African archive, producing a more inclusive history for humanity than that produced by the seemingly lofty ideals of national and international space laws.
Populism, Constitutional Counter-Narratives and Comparative Law
Authors: Martinico Giuseppe
Published: February 2021

This article tries to explore the relationship between constitutionalism and populism in conceptual terms. This piece is divided into two parts. In the first part it will be argued that the relationship between populism and constitutionalism should not be seen in terms of mutual exclusion and perfect opposition. In the second part I shall look at comparative law in order to explore its incredible anti-populist potential. More in general, as I shall try to explain, the very idea of populist constitutionalism is not consistent with the legacy of post-wwii constitutionalism.
Two new genera and species of Fidicinini Distant, 1905 with a re-description of Nosola Stål, 1866 (Hemiptera, Auchenorrhyncha, Cicadidae)
Authors: RUSCHEL TATIANA P. , SANBORN ALLEN F.
Published: February 2021

The cicada genus Nosola Stål, 1866 and its type species N. paradoxa Stål, 1866 are described fully for the first time. Two Neotropical Fidicinini Distant, 1905 related to Nosola are described as new genera and species. Nosoarna albipilosa n. gen., n. sp. from Brazil and Rhaeboepelis takiyaae n. gen., n. sp. from Costa Rica are described and illustrated.
Konowia Brauns, 1884, and Monoxiphia, n. gen. (Hymenoptera, Xiphydriidae): Palaearctic woodwasps with simple tarsal claws on all legs
Authors: SHINOHARA AKIHIKO , HARA HIDEHO
Published: February 2021

The Palaearctic xiphydriid genus Konowia Brauns, 1884, is redefined and the component species are revised on the basis of a close examination of stability and taxonomic use of previously used and newly introduced characters. A new genus, Monoxiphia, is proposed for Konowia harai Shinohara, 2019, from Japan (Monoxiphia harai (Shinohara, 2019), n. comb.) and Xiphydriola Semenov-Tian-Shanskij, 1921, is synonymized with Konowia. Konowia is represented by the following four species: K. betulae (Enslin, 1911) from Europe, through Siberia, Korea to Japan (Hokkaido, Kunashiri Is.), K. kojimai, n. sp., from Japan (Hokkaido, Honshu), K. megapolitana Brauns, 1884 from Europe to the Russian Far East, and K. yasumatsui (Togashi, 1972) from Japan (Honshu, Shikoku, Kyushu). Xiphydriola amurensis Semenov-Tian-Shanskij, 1921, and Platyxiphydria nishijimai Togashi, 1998, are synonymized with K. betulae and a new species, K. kojimai, is described from Japan. Konowia yasumatsui is newly recorded from Honshu and Shikoku and the male of this species is described for the first time. A key to separate Monoxiphia, Konowia and four Konowia species is provided.