tbuckley/cabot-search huggingface dataset:
Abstract LB-161: Application of the ASCO and ESMO frameworks to TTFields treatment of mesothelioma
Authors: Justin Kelly, Uri Weinberg, Christina Proescholdt
Journal: Cancer Research (2019)

Abstract Objective: To assess the clinical value of tumor treating fields (TTFields) in malignant pleural mesothelioma (MPM) by means of the ASCO and ESMO frameworks. Background: The potential effectiveness and safety of TTFields in addition to pemetrexed and cisplatin or carboplatin in MPM was recently shown by the analysis of the Phase II single arm EF-23 STELLAR trial. To account for the need of physicians and policymakers to objectively and comparably capture the clinical value of new cancer treatments the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have both developed assessment frameworks. We quantified the clinical value of the TTFields treatment in MPM by applying ASCO and ESMO frameworks to the comparison of the STELLAR data to historical controls. Materials/Methods: The EF-23 STELLAR Trial (n=80) demonstrated that adding TTFields to pemetrexed and cisplatin or carboplatin for malignant pleural mesothelioma patients resulted in overall survival of 18.2 months (95% CI 12.1-25.8) and progression free survival of 7.6 months (95% CI 6.7-8.6). The ESMO Magnitude of Clinical Benefit Scale (MCBS) and the ASCO Net Health Benefit (NHB) frameworks were applied to the EF-23 trial data using a historical control as comparator. Results: The application of the ASCO framework to the EF-23 data resulted in a NHB score of 52. This result was at the higher end of the score range of novel cancer treatments and compares well to the results for nivolumab in advanced non-squamous NSCLC and advanced squamous NSCLC as reference points. Applying the ESMO framework resulted in MCBS scores of A/5 (adjuvant/advanced) which would be the first score reported for MPM. The MCBS scores of A/5 are the highest scores achievable in the ESMO framework, and higher then the ESMO MCBS scores reported in the literature for NSCLC treatments. Conclusions: Despite differences in their respective concepts, both the ASCO and ESMO frameworks suggest that adding TTFields to Pemetrexed and Cisplatin or Carboplatin in malignant pleural mesothelioma patients may provide a significant clinical benefit. The high scores underline the fact that treatment with TTFields may extended progression free and overall survival without additional systemic toxicities. Citation Format: Justin Kelly, Uri Weinberg, Christina Proescholdt. Application of the ASCO and ESMO frameworks to TTFields treatment of mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-161.
Exploratory analysis of the effect of FTD/TPI in mCRC patients treated in RECOURSE by different prognostic factors: impact on ECOG PS
Authors: G. Argiles, J. Tabernero, A. Sobrero, A. Ohtsu, R. Mayer, L. Vidot, S. Moreno Vera, E. Van Cutsem
Journal: Annals of Oncology (2019)
Abstract 4100: Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy
Authors: Devika Ashok, Songming Peng, Benjamin Yuen, Matt Walters, Stephen W. Young, Lisa Seitz
Journal: Cancer Research (2019)

Abstract Background: In patients undergoing chemotherapy and/or immune therapy, endogenous T cells within the tumor micro-environment (TME) and in the periphery are subject to dynamic changes. Particularly, exhausted T cells in the TME and peripheral blood mononuclear cells (PBMCs) isolated from whole blood express the inhibitory receptor, Programmed Cell Death Receptor 1 (PD-1). A small but significant number of these T cells can recognize neo-epitopes (neoE) arising from patient specific mutations. We determined receptor occupancy (RO) in patients treated with monoclonal anti-PD-1 antibody AB122, which is currently in clinical development. Methods: Multi-color flow cytometry was used to determine RO post-AB122 administration using a directly-conjugated competitive antibody to AB122. In addition, we determined RO values using the established method for nivolumab using a biotinylated anti-human IgG4 to detect bound anti-PD-1. The assays were also optimized to determine RO in whole blood from patients with solid tumors treated with AB122. Receptor occupancy using both methods were compared. Further, whole exome sequencing from archival formalin-fixed, paraffin-embedded (FFPE) tissue was performed and T cells that recognized patient-specific neoE resulting from tumor-specific mutations were identified in patient blood. Results: In the dose-escalation study for AB122 monotherapy arm, a variety of dosing regimens have been evaluated, including Q2W, Q3W and Q4W. The number of doses received ranged from 1 to 20. Data from patients in the 80 and 240 mg Q2W cohorts showed that AB122 serum concentrations ≥1.5 μg/mL (equivalent to 10 nM) are associated with full receptor occupancy. The RO associated with AB122 dosing is maintained when dosed in combination with the potent A2aR/A2bR dual adenosine receptor antagonist AB928 in an ongoing clinical trial. Conclusions: Full RO is observed with both cohorts of AB122 monotherapy (80 and 240 mg Q2W) and in the 240 mg Q2W combination with AB928. Study of peripheral target engagement and expansion of neoE-specific T cell populations in a longitudinal study of solid tumor patients treated with AB122 could provide insight towards designing successful combination immune therapy regimens in future clinical trials with AB122. Citation Format: Devika Ashok, Songming Peng, Benjamin Yuen, Matt Walters, Stephen W. Young, Lisa Seitz. Receptor occupancy and neo-epitope specific T-cell repertoires in patients with solid tissue tumors following anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4100.
Racial disparities in survival of glioblastoma patients not treated with radiation.
Authors: Jigisha P. Thakkar, Therese A. Dolecek, Andra M Popa, John L. Villano
Journal: Journal of Clinical Oncology (2013)

2069 Background: Race-based outcomes have been documented for inpatient hospital care for glioblastoma (GBM), however, SEER-based population studies do not replicate the differences in race for outcomes in GBM. Moreover, most advanced cancers demonstrate differences in race based outcomes. We hypothesized that there is a difference in race based outcomes for GBM with advanced clinical involvement preventing an established standard of care such as radiation therapy (RT). Methods: We analyzed survival estimates and procedure frequencies by race for GBM patients (n=4931) 20 years and older, not treated with radiation in the initial round of therapy; from 2000-2008, using the Surveillance, Epidemiology, and End Results (SEER) 17 registries database and listed them by surgery type. Kaplan–Meier relative survival rates were calculated by surgery type and race group (blacks and whites) followed by evaluation of association between race and survival rate. Race comparisons were limited to 1 year because of small numbers in the subgroups. Results: We found no statistically significant support for a racial disparity in survival among GBM patients with different surgical interventions (tumor destruction/biopsy, partial or total resection). However, for those receiving no surgery (and no RT), blacks actually had better one-year survival than whites. By surgery, those receiving gross total resection had higher survival in both blacks and whites. In whites only, any type of surgery (tumor destruction/biopsy, partial or total resection) had better survival than none. Conclusions: Overall, there are no statistically significant differences between blacks and whites in terms of survival in GBM patients not receiving RT in the initial round of therapy. Differences in race based care for GBM have not been found outside of inpatient hospital based care, which is unusual for an aggressive cancer needing specialized multi-modality care. [Table: see text]
A Phase II Study of Brentuximab Vedotin for Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas Other Than Anaplastic Large Cell Lymphoma
Authors: Silvia Park, Seok Jin Kim, Jung Yong Hong, Dok Hyun Yoon, Jin Seok Kim, Hye Jin Kang, Hyeon-Seok Eom, Mark Hong Lee, Cheolwon Suh, Won Seog Kim
Journal: Blood (2017)
Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation
Authors: Eleftheria Papaioannou, Diana C. Yánez, Susan Ross, Ching-In Lau, Anisha Solanki, Mira Manilal Chawda, Alex Virasami, Ismael Ranz, Masahiro Ono, Ryan F. L. O’Shaughnessy, Tessa Crompton
Journal: Journal of Clinical Investigation (2019)

Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin, and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor-β (TGF-β) in Tregs signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4+ T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4+ T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven Treg cell-mediated immune suppression, paving the way for a potential new therapeutic strategy.
<i>BJD</i> : a global dermatology journal serving the needs of its readers worldwide
Authors: E. Linos, N. Rajan, J.R. Ingram
Journal: British Journal of Dermatology (2019)

The field of dermatology aims to improve the lives of all patients with skin disease. As the incoming editors of the BJD we see this as one of our key responsibilities. This is a challenge because too often medical research, educational resources and funding opportunities do not represent certain groups. For example, racial minorities1 and women2 are under‐represented in dermatological clinical trials. Skin of colour is not adequately included in dermatology textbooks3 or machine‐learning algorithms focused on skin cancer detection.4 Systematic reviews often exclude studies published in languages other than English.5 Low‐resource countries receive fewer dermatology services and the skin diseases affecting their populations get less scientific attention compared with those more prevalent in resource‐rich settings.6 There is an urgent need to broaden the scope and diversity of dermatological research in order to improve dermatology care globally. The BJD has been steadily growing as a global leader in dermatology publishing, with readership and institutional subscriptions spanning the world. As of 2018, 97% of institutional subscriptions to the journal came from institutions outside the U.K. This includes 7006 institutions providing standard BJD access and an additional 7911 institutions in developing countries receiving low‐cost or free access. The BJD readership also reflects the international appeal of the journal. In 2018, 90% of BJD article downloads took place outside the U.K.: 23% in the U.S.A., 7% in China, 5% in Japan, 4% in each of Germany, India and Australia, 3% in each of France, the Netherlands and South Korea, and 34% in other countries around the world.
Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia.
Authors: Iman Aboudalle, Ronald Paranal, Shilpa Paul, Wen Li, Jing Ning, Jorge E. Cortes, Elias Jabbour, Hagop M. Kantarjian, Ghayas C. Issa
Journal: Journal of Clinical Oncology (2019)

7039 Background: Treatment of acute leukemia with intensive chemotherapy (IC) leads to increased risk of infection and bleeding because of myelosuppression. Luteinizing hormone (LH) blockade was found to improve hematopoietic recovery in mice after radiation or chemotherapy through protection of the hematopoietic stem cells (HSCs) which express the LH receptor (Velardi et al, Nat Med 2018). We hypothesized that LH blockade improves hematopoietic recovery following IC in patients (pts) with leukemia. Methods: We assessed gene expression of the LH receptor (LHR) in lineage-specific normal and AML hematopoietic cells from a reference dataset (Corces et al, Nat Gen 2016). We conducted a retrospective analysis on pre-menopausal women with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) who received IC and Lupron, given for prevention or treatment of abnormal uterine bleeding. Results: LHR was greatest in HSCs, with little or no expression in mature subtypes within the hematopoietic hierarchy. Surprisingly, LHR was expressed on blasts. Since Lupron was more commonly given in younger pts, we performed propensity matching between the Lupron groups (AML N = 64; ALL N = 49) and control (Ctrl) groups (AML N = 128; ALL N = 98 pts). Baseline characteristics including blood counts were well balanced. Pts with AML who had received Lupron had a significantly higher increase in their platelet count following IC (13.8x10 9 /L/year vs Ctrl; p = 0.02). Pts with ALL who had received Lupron had significantly higher increase in their absolute neutrophil count (0.37x10 9 /L/year vs Ctrl; p = 0.02). AML pts in the Lupron group received significantly less blood transfusions vs Ctrl (mean: 23.9 vs 34.7 units; P = 0.002) and less platelet transfusions (mean: 24.4 vs 32.8 units; P = 0.06). There was no difference in event-free and overall survival between the groups in each leukemia cohort. Conclusions: Lupron use in leukemia pts receiving IC was associated with improved long-term blood count recovery. It was also associated with decreased transfusion requirements in AML. Despite expression of the LHR in blasts in addition to normal HSCs, there was no effect of LH blockade on rates of leukemia relapse or death.
Symptom clusters in newly diagnosed glioma patients: which symptom clusters are independently associated with functioning and global health status?
Authors: Marijke B Coomans, Linda Dirven, Neil K Aaronson, Brigitta G Baumert, Martin Van Den Bent, Andrew Bottomley, Alba A Brandes, Olivier Chinot, Corneel Coens, Thierry Gorlia, Ulrich Herrlinger, Florence Keime-Guibert, Annika Malmström, Francesca Martinelli, Roger Stupp, Andrea Talacchi, Michael Weller, Wolfgang Wick, Jaap C Reijneveld, Martin J B Taphoorn
Journal: Neuro-Oncology (2019)

Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients' functioning.Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders.Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5-10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (≥10 points difference) physical, role, and social functioning (betas ranged from -11.3 to -15.9, all P < 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of -12.3, P < 0.001), independent of other factors.Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients' functioning as measured with a self-report questionnaire.
New radiological diagnostic criteria: impact on idiopathic pulmonary fibrosis diagnosis
Authors: Manuela Funke-Chambour, Sabina A. Guler, Thomas Geiser, Andreas Christe, Johannes Heverhagen, Alexander Pöllinger, Adrian Huber, Lukas Ebner
Journal: European Respiratory Journal (2019)

<b>Divergent recommendations and guidelines exist for IPF. Comparison of existing guidelines indicates IPF was diagnosed with better sensitivity and preserved specificity with Fleischner recommendations compared with current clinical practice guidelines.</b>http://bit.ly/2ozH9la
Abstract 2634: The role of Eph A receptor 3 tyrosine kinase signaling in prostate cancer progression
Authors: Marwah M. Al-Mathkour, Bekir Cinar
Journal: Cancer Research (2019)

Abstract Dysregulation of the receptor tyrosine kinases (RTKs) by means of mutation, amplification or overexpression plays a crucial role in cell growth, cell survival, cell motility during cancer progression and metastasis. EPHA3 (erythropoietin-producing hepatocellular carcinoma cell surface type A receptor 3) is a member of the RTKs. Evidence indicates that the upregulation of the EPHA3 activity is implicated in the pathobiology of various cancers, including prostate cancer, and thus, it is a prime therapeutic target in cancer. However, the role of EPHA3 signaling in prostate cancer progression remains obscure. Currently, the development of castration-resistant prostate cancer (CRPC) poses a clinical challenge because it is lethal. The molecular mechanisms that contribute to lethal prostate cancer are largely unknown. The objective of this study is to investigate whether EPHA3 signaling plays a critical role in prostate cancer progression and therapeutic relapse. Our analysis of the prostate cancer public datasets revealed that the EPHA3 gene was amplified up to 19% of metastatic CRPC cases with the neuroendocrine phenotype. Our immunological assay confirmed the positive staining of EPHA3 protein in human prostate cancer specimens. Our semi-quantitative and quantitative PCR assays demonstrated that the levels of EPHA3 varies among established prostate cancer cell lines. Nevertheless, we consistently found that the levels of EPHA3 mRNA in CRPC cell line, C4-2, were 3-fold higher than its castration-sensitive parental LNCaP cells. Furthermore, we demonstrated that increase in expression of EPHA3 mRNA in C4-2 compared with LNCaP cells coincided with the upregulation of the EPHA3 protein, as independently confirmed by western blotting and immunofluorescence imaging. These findings indicate that EPHA3 may confer an aggressive prostate cancer cell phenotype. Because androgen receptor (AR) signaling is a potent mediator of CRPC cell growth and survival, the targeting of EPHA3 signaling alone or together with AR may improve the efficacy of current therapies for patients with advanced prostate cancer. Citation Format: Marwah M. Al-Mathkour, Bekir Cinar. The role of Eph A receptor 3 tyrosine kinase signaling in prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2634.
Periodontitis-induced systemic inflammation exacerbates atherosclerosis partly via endothelial–mesenchymal transition in mice
Authors: Jin Sook Suh, Sol Kim, Kristina I. Boström, Cun-Yu Wang, Reuben H. Kim, No-Hee Park
Journal: International Journal of Oral Science (2019)

Growing evidence suggests close associations between periodontitis and atherosclerosis. To further understand the pathological relationships of these associations, we developed periodontitis with ligature placement around maxillary molars or ligature placement in conjunction with Porphyromonas gingivalis lipopolysaccharide injection at the ligature sites (ligature/P.g. LPS) in Apolipoprotein E knock out mice and studied the atherogenesis process in these animals. The mice were fed with high fat diet for 11 weeks and sacrificed for analyzing periodontitis, systemic inflammation, and atherosclerosis. Controls did not develop periodontitis or systemic inflammation and had minimal lipid deposition in the aortas, but mice receiving ligature or ligature/P.g. LPS showed severe periodontitis, systemic inflammation, and aortic plaque formation. The aortic plaque contained abundant macrophages and cells expressing both endothelial and mesenchymal cell markers. The severity of periodontitis was slightly higher in mice receiving ligature/P.g. LPS than ligature alone, and the magnitude of systemic inflammation and aortic plaque formation were also notably greater in the mice with ligature/P.g. LPS. These observations indicate that the development of atherosclerosis is due to systemic inflammation caused by severe periodontitis. In vitro, P.g. LPS enhanced the secretion of pro-inflammatory cytokines from macrophages and increased the adhesion of monocytes to endothelial cells by upregulating the expression of adhesion molecules from endothelial cells. Moreover, secretory proteins, such as TNF-α, from macrophages induced endothelial-mesenchymal transitions of the endothelial cells. Taken together, systemic inflammation induced by severe periodontitis might exacerbate atherosclerosis via, in part, causing aberrant functions of vascular endothelial cells and the activation of macrophages in mice.
Abstract 807: HDAC1 -dependent epigenetic loss of ATP5H confers a stem cell-like phenotype with features associated with metastatic capacity through mitochondrial reprogramming
Authors: Suyeon Kim, Kwon-Ho Song, Tae-Woo Kim
Journal: Cancer Research (2019)

Abstract The failure of most cancer therapies is the emergence of tumor cells that are refractory to available agent. Here we report that single-modality cancer therapy triggers broad-spectrum cross-resistance to multiple clinical interventions. This multi-modality resistance arises through a core metabolic reprogramming pathway instigated by loss of the ATP synthase subunit ATP5H, which sequentially leads to accumulation of reactive oxygen species and stabilization of HIF-1α under normoxia. Furthermore, we found that NANOG/HDAC1 axis regulates epigenetic loss of ATP5H, this pathway confers tumor cells a stem cell-like phenotype with features associated with metastatic capacity. ATP5H loss in the tumor is strongly linked to failure of therapy, and poor survival in cancer patients. Integration of these biological features provides the best basis for understanding patient outcome in this setting and suggests that loss of ATP5H shapes the tumor resistance to multiple anti-tumor therapy. Citation Format: Suyeon Kim, Kwon-Ho Song, Tae-Woo Kim. HDAC1 -dependent epigenetic loss of ATP5H confers a stem cell-like phenotype with features associated with metastatic capacity through mitochondrial reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 807.