tbuckley/cabot-search huggingface dataset:
Abstract 2086: Differential immune-cell landscape in tissue and liquid biopsy specimens is associated with recurrence risk across meningioma methylation-subtypes
Authors: Grayson A. Herrgott
Journal: Cancer Research (2021)

Abstract Background. Tumor-infiltrating immune cells can favor or inhibit tumor growth, constituting promising and alternative targets for treatment of patients with meningiomas (MNG), a prevalent primary intracranial tumor with no known therapy beyond surgery and radiation. Immune-cell composition can predict therapy response in other diseases, therefore, profiling immune-cell infiltrates in these tumors is crucial, preferentially by non-invasive approaches. Genome-wide methylation arrays are powerful tools to classify and assess cell composition either in tumor tissue or with liquid biopsy. Objective: We aim to apply methylation-based classifiers to estimate immune-cell composition of tumor tissue and serum specimens to predict recurrence-free survival in patients with MNG. Methods: We conducted unsupervised and supervised analyses of the methylome of a multicenter MNG cohort composed of 326 tissue, 60 serum and 9 control specimens. Immune-cell composition (B-cells, CD4-T &amp; CD8-T cells, neutrophils, natural killer cells, and monocytes) and recurrence risk were estimated using methylation-based classifiers. We used the point-biserial correlation method to analyze associations across categorical clinical and molecular features. Results: We identified four distinct methylation subgroups of MNG (in serum or tissue) that presented a differential immune cell landscape composition. In the tissue, MNG methylation subgroups were mutually exclusive in enrichment or depletion of NK-, cytotoxic T- or monocyte-cell methylation signatures and in the serum, they were enriched of monocyte- and B-cell signatures. Distinct Immune-cell signatures (Monocytes, CD8T and Neutrophils) were correlated with risk of recurrence or grade in MNG tissue and/or liquid biopsy specimens. Conclusion: DNA methylation-based deconvolution allowed for the detection of differential immune-cell composition across MNG methylation-subtypes in tissue that could be detected in liquid biopsy specimens. Distinct immune-cell signatures correlated with MNG recurrence risk/grade (e.g. T-cell) in our cohort were reported to improve anti-tumoral immune response in many tumors. These results suggest that profiling tumor immune-cell landscape can inform tumor behavior and provide insight in application of existing and novel therapeutic approaches in MNG. Citation Format: Grayson A. Herrgott. Differential immune-cell landscape in tissue and liquid biopsy specimens is associated with recurrence risk across meningioma methylation-subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2086.
GFR fluctuation induced by neoadjuvant chemotherapy correlates with pathologic stage of upper tract urothelial carcinoma
Authors: P.J. Hensley, T. Miest, M. Adibi, M. Campbell, A. Shah, L. Cherry, J. Papadopoulos, A. Siefker-Radtke, J. Gao, C. Guo, B. Czerniak, N. Navai, A. Kamat, C. Dinney, S. Matin
Journal: European Urology (2021)
SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non–Small-Cell Lung Cancer—A Multicenter Single-Arm Phase II Trial
Authors: Sacha I. Rothschild, Alfred Zippelius, Eric I. Eboulet, Spasenija Savic Prince, Daniel Betticher, Adrienne Bettini, Martin Früh, Markus Joerger, Didier Lardinois, Hans Gelpke, Laetitia A. Mauti, Christian Britschgi, Walter Weder, Solange Peters, Michael Mark, Richard Cathomas, Adrian F. Ochsenbein, Wolf-Dieter Janthur, Christine Waibel, Nicolas Mach, Patrizia Froesch, Martin Buess, Pierre Bohanes, Gilles Godar, Corinne Rusterholz, Michel Gonzalez, Miklos Pless
Journal: Journal of Clinical Oncology (2021)

For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab.Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m2 and docetaxel 85 mg/m2 once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%.Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related.The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.
Bacteraemia and bacteria spread into the irrigation fluid during percutaneous nephrolithotomy: A prospective study
Authors: E. De Lorenzis, C. Bebi, C. Silvani, L. Boeri, F. Ripa, E. Lievore, A. Gallioli, M. Turetti, G. Lucignani, L. Rocchini, F. Longo, A. Teri, A. Dodaro, C. Vignati, C. Matinato, R. Colombo, E. Montanari
Journal: European Urology (2021)
Abstract 2871: Hypermetastatic stem-like cells from 'cancer of unknown primary' (CUP) model multi-organ dissemination and unveil liability to MEK inhibition
Authors: Federica Verginelli, Alberto Pisacane, Gennaro Gambardella, Antonio D'Ambrosio, Ermes Candiello, Marco Ferrio, Mara Panero, Laura Casorzo, Silvia Benvenuti, Eliano Cascardi, Rebecca Senetta, Elena Geuna, Andrea Ballabio, Filippo Montemurro, Anna Sapino, Paolo M. Comoglio, Carla Boccaccio
Journal: Cancer Research (2021)

Abstract Cancers of Unknown Primary (CUPs), featuring metastatic dissemination in the absence of a primary tumor, anatomically or histologically recognizable through a standardized work-up, are a fatal disease and still a biological enigma. Here, we propose CUPs as a distinct, yet unrecognized, pathological entity originating from stem-like cells endowed with unique properties, irrespective of their different genetic backgrounds. These cells were isolated and long-term propagated in vitro in highly stringent conditions as ‘agnospheres', and serially transplanted in vivo, displaying an extremely high tumorigenic potential and reproducing the undifferentiated histology of the original tumors. Early after subcutaneous engraftment, agnospheres recapitulated the CUP clinical presentation, as they spontaneously and quickly disseminated, establishing widespread metastases and retracing the whole metastatic cascade. Agnospheres invariably displayed cell-autonomous proliferation and self-renewal, mostly relying on unrestrained activation of the MAP kinase/MYC axis. This feature conferred sensitivity to MEK inhibitors, which induced apoptosis in vitro and impaired in vivo growth and dissemination. We generated and validated a transcriptional signature that, applied to original tumors, predicts eligibility to MEK inhibition in 75% of CUP patients. Altogether, these findings shed light on CUP biology, unveiling an opportunity for a targeted therapeutic intervention and, concomitantly, provide a novel in vivo model, suitable for assessing molecular determinants of the metastatic cascade. Citation Format: Federica Verginelli, Alberto Pisacane, Gennaro Gambardella, Antonio D'Ambrosio, Ermes Candiello, Marco Ferrio, Mara Panero, Laura Casorzo, Silvia Benvenuti, Eliano Cascardi, Rebecca Senetta, Elena Geuna, Andrea Ballabio, Filippo Montemurro, Anna Sapino, Paolo M. Comoglio, Carla Boccaccio. Hypermetastatic stem-like cells from 'cancer of unknown primary' (CUP) model multi-organ dissemination and unveil liability to MEK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2871.
Abstract LB196: Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer
Authors: Neal Shiv Chawla, Zeynep Zengin, Ameish Govindarajan, Sumanta K. Pal
Journal: Cancer Research (2021)

Abstract Background: Next generation sequencing (NGS) to identify genomic alterations (GAs) in tumor samples are increasingly used in clinical practice. Targeted sequencing (TS) or whole exome sequencing (WES) are used by various commercially available platforms. Differing methods often result in poor inter-reproducibility, even when testing the same tissue. Bladder cancer has substantial genetic heterogeneity as compared to many other malignancies. The purpose of this study is to compare WES and TS in bladder cancer. Methods: Patients with advanced bladder cancer who had undergone tissue WES (GEM ExTra®) or TS (FoundationOne CDx® [FMI]) in the course of routine clinical care were assessed. Genes with at least one detected GA were selected, with others excluded. All detected GAs were classified as being detected on TS only, WES only, concordant (detected on both platforms), or partially concordant (different GAs detected within the same gene). Variants of uncertain significance were excluded for this study. Results: In our series, 25 patients had WES and 42 patients had TS - 14 patients (21%) had both tests performed. A total of 88 genes were detected to have at least one GA across all samples. Of all detected GAs, 66/162 (41%) were concordant, with 45/162 (28%) and 51/162 (31%) of GAs detected exclusively by WES and TS, respectively. The genes with the highest proportion of concordance when detected, were TERT (70%), TP53 (85%) and ARIDA1A (50%). SOX4 and E2F3 were detected on WES only, while RBM and CHEK2 were detected on TS only. Notably, six TP53 GAs were detected exclusively on TS. TP53, TERT, MLL2/KMT2D, ERBB2 were each partially concordant on one occasion. The difference in the rate of concordant GAs in samples from the same collection site and date (41%), as compared to those in which both differed (35%) were not statistically significant (p=0.54). Conclusions: Although the majority of GAs identified were concordant, each platform exclusively identified GAs with varying clinical significance. SOX4 and E2F3 mutation, shown to correlate with invasive potential in bladder cancer, were detected exclusively on WES. In contrast, RBM and CHEK2 (of known significance in melanoma and breast cancer) were found exclusively on TS. Larger series are needed to further establish the concordance of these approaches. Citation Format: Neal Shiv Chawla, Zeynep Zengin, Ameish Govindarajan, Sumanta K. Pal. Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB196.
Abstract 2849: Shc1 as a potential metastasis driver gene of breast cancer
Authors: Megan Majocha, Kent Hunter, Christina Ross
Journal: Cancer Research (2021)

Abstract In the US, women diagnosed with non-metastatic breast cancer have a 5-year survival rate of approximately 98.8%. However, if women develop metastases the survival rate drops to 27.4%, highlighting the need for a better understanding of the mechanisms that regulate and drive metastasis. Somatically acquired mutations that drive metastasis were originally hypothesized by Nowell in the 1970s; however, to date few candidate metastasis driver mutations have been identified and the role of these mutations in metastasis are not well-understood. Using the PyMT genetically engineered mouse model of luminal metastatic breast cancer, previous work by our group performed whole exome sequencing on pairs of matched primary tumor and metastatic tissues from 65 mice. Analysis of this sequencing data identified recurrent metastasis-specific mutations in members of the Ras signaling pathway. One of the members was the SHC Adaptor Protein 1 (Shc1). Five PyMT animals carried different nucleotide substitutions within the same proline 561 codon that falls within the SH2 domain, suggesting an activating role in metastasis. Furthermore, changing this proline mutation to another amino acid could induce a critical change to the Shc1 protein structure and its function. To investigate the role of Shc1 in breast cancer metastasis, CRISPR was performed engineer Shc1 P561 mutations for in vitro and in vivo assays using a series of mouse mammary cancer cell lines and allograft mouse models. Preliminary evidence suggests the P561 mutations have a role in metastasis. Future experiments will address the consequences of the P561 mutation on Shc1 binding partner interactions and downstream signaling and its effects on breast cancer metastasis. Citation Format: Megan Majocha, Kent Hunter, Christina Ross. Shc1 as a potential metastasis driver gene of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2849.
The role of Kingella kingae in pre-school aged children with bone and joint infections
Authors: Laudi Olijve, Lahiru Amarasena, Emma Best, Christopher Blyth, Mirjam van den Boom, Asha Bowen, Penelope A. Bryant, Jim Buttery, Hazel C. Dobinson, Joshua Davis, Joshua Francis, Heidi Goldsmith, Elle Griffiths, Te-Yu Hung, Julie Huynh, Alison Kesson, Andrea Meehan, Brendan McMullan, Clare Nourse, Pamela Palasanthiran, Rushi Penumarthy, Katie Pilkington, Janine Searle, Anya Stephenson, Rachel Webb, Jonathan Williman, Tony Walls
Journal: Journal of Infection (2021)
Is a New Era Coming for Bronchopulmonary Dysplasia Prevention With Corticosteroids?—Reply
Authors: Viraraghavan Vadakkencherry Ramaswamy, Charles Christoph Roehr
Journal: JAMA Pediatrics (2021)

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Abstract 1194: MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer
Authors: Athena M. Apfel, Nathan M. Merrill, Nathalie M. Vandecan, Liwei Bao, Xu Cheng, Lluis A. Lopez-Barcons, Kathleen C. Day, Phillip L. Palmbos, Mark L. Day, Aaron M. Udager, Matthew B. Soellner, Sofia D. Merajver
Journal: Cancer Research (2021)

Abstract There are diverse resources available for data relevant to the drug screening of bladder cancer cell lines in 2D culture, such as the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases; however, 3D culture is more representative of in vivo response in patients. Moreover, drug screens in 3D reveal differential drug response and expression of genes and proteins that indicate the potential of more effective selection of drugs for specific patients: the basic tenet of personalized oncology. Therefore, we screened bladder cancer cell lines in 3D culture using a library of curated small-molecule inhibitors to identify compounds and classes of compounds with efficacy in bladder cancer. Genomic and transcriptomic data for these bladder cancer cell lines were used to correlate genomic molecular parameters with drug response with the aim of discerning biomarkers of response or to suggest plausible drug combinations. This allowed us to identify groups of tumors that are vulnerable to specific drugs or classes of drugs. We found that MEK inhibitors were a promising target among basal bladder cancers, an RNA-based molecular subtype of bladder cancer, especially aggressive and exhibiting poor prognosis. Furthermore, trametinib was found to be a “very active” MEK inhibitor in basal cancers, classified using drug sensitivity 3 (DSS3) scoring. PI3K/AKT/MTOR inhibitors target a parallel signaling pathway to MEK inhibition; therefore, we tested PI3K/AKT/MTOR combinations with trametinib in basal bladder cancer to query for synergistic properties. Additionally, we tested PI3K/AKT/MTOR combinations with trametinib using ex vivo organoids of bladder cancer patient samples collected directly at operation. Taken together, MEK inhibition is a promising therapeutic strategy in the basal subtype of bladder cancer, particularly in combination with parallel pathway inhibition. Moving forward, we plan to test PI3K/AKT/MTOR combinations with trametinib in trametinib-resistant basal bladder cancer cell lines to investigate how this affects signaling and re-sensitization to trametinib. Citation Format: Athena M. Apfel, Nathan M. Merrill, Nathalie M. Vandecan, Liwei Bao, Xu Cheng, Lluis A. Lopez-Barcons, Kathleen C. Day, Phillip L. Palmbos, Mark L. Day, Aaron M. Udager, Matthew B. Soellner, Sofia D. Merajver. MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1194.
Treatment outcomes of bladder stones in children: A systematic review of &gt;1000 cases on behalf of the European Association of Urology Urolithiasis Guideline Panel
Authors: N.D. Davis, J. Donaldson, A. Neisius, A. Petrik, C. Seitz, K. Thomas, R. Lombardo, L. Tzelves, B. Somani, G. Gambaro, A. Skolarikos, C. Turk
Journal: European Urology (2021)
Incorporating SGLT2i and GLP-1RA for Cardiovascular and Kidney Disease Risk Reduction: Call for Action to the Cardiology Community
Authors: Adam J. Nelson, Neha J. Pagidipati, Vanita R. Aroda, Matthew A. Cavender, Jennifer B. Green, Renato D. Lopes, Hussein Al-Khalidi, Tanya Gaynor, Lisa A. Kaltenbach, Julienne K. Kirk, Ildiko Lingvay, Melissa L. Magwire, Emily C. O’Brien, Jonathan Pak, Rodica Pop-Busui, Caroline R. Richardson, Monica Reed, Cagri Senyucel, Laura Webb, Darren K. McGuire, Christopher B. Granger
Journal: Circulation (2021)

Multiple sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to impart significant cardiovascular and kidney benefits, but are underused in clinical practice. Both SGLT-2i and GLP-1RA were first studied as glucose-lowering drugs, which may have impeded uptake by cardiologists in the wake of proven cardiovascular efficacy. Their significant effect on cardiovascular and kidney outcomes, which are largely independent of glucose-lowering effects, must drive a broader use of these drugs. Cardiologists are 3 times more likely than endocrinologists to see patients with both type 2 diabetes and cardiovascular disease, thus they are ideally positioned to share responsibility for SGLT-2i and GLP-1RA treatment with primary care providers. In order to increase adoption, SGLT-2i and GLP-1RA must be reframed as primarily cardiovascular and kidney disease risk-reducing agents with a side effect of glucose-lowering. Coordinated and multifaceted interventions engaging clinicians, patients, payers, professional societies, and health systems must be implemented to incentivize the adoption of these medications as part of routine cardiovascular and kidney care. Greater use of SGLT-2i and GLP-1RA will improve outcomes for patients with type 2 diabetes at high risk for cardiovascular and kidney disease.
Abstract 1211: Anti-LSR mAb with carboplatin shows the synergistic effect in epithelial ovarian cancer
Authors: Masashi Funauchi, Kosuke Hiramatsu, Satoshi Serada, Minoru Fujimoto, Tetsuji Naka
Journal: Cancer Research (2021)

Abstract Objectives : Previously, we demonstrated anti-cancer effect of our newly developed monoclonal antibody (mAb) targeting lipolysis-stimulated lipoprotein receptor (LSR) in LSR-positive epithelial ovarian cancer (EOC) in vitro and in vivo. In EOC treatment, platinum agents which induce apoptosis are the key drugs over the decades, therefore, we aimed to demonstrate the synergistic effect of anti-LSR mAb and platinum agent against LSR-positive EOC cells. Methods : We administrated anti-LSR mAb and carboplatin to RMG-I cells (platinum resistant and LSR-positive EOC cell line) and evaluated cell proliferation in vitro and in vivo. We also investigated whether anti-LSR mAb reverse platinum resistance of RMG-I in vitro. In addition, we analyzed changes in protein expression related to MAPK/ERK and apoptosis using western blotting after treatment. Results : In RMG-I, anti-LSR mAb inhibited phosphorylation of MAPK pathway-related proteins including MEK and ERK, and activated apoptosis-related proteins. Although RMG-I showed the refractory for carboplatin, anti-LSR mAb reversed its platinum resistance and decreased IC50 value of carboplatin. As a result, anti-LSR mAb induced the apoptotic effect of carboplatin in RMG-I. Finally, the combination therapy of anti-LSR mAb and carboplatin significantly inhibited the tumor growth of RMG-I in a synergistic manner in vitro and in vivo (p&amp;lt;0.05). The combination therapy caused strong apoptotic changes in tumor. Conclusions : We confirmed the synergistic effect of the combination therapy of anti-LSR mAb and platinum agent against LSR-positive EOC cells via apoptotic pathway. Our findings demonstrated that this combination therapy might be a new treatment option of EOC. Citation Format: Masashi Funauchi, Kosuke Hiramatsu, Satoshi Serada, Minoru Fujimoto, Tetsuji Naka. Anti-LSR mAb with carboplatin shows the synergistic effect in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1211.