tbuckley/cabot-search huggingface dataset:
A methodological framework for establishing a translational research accelerator (TRA) for cancer research.
Authors: Hannah Beird, Jennifer Brooke Goldstein, Jianjun Zhang, Chris Belmont, Bryan Lari, Prabal Basu, Dhiraj Pathak, Robert Fassett, Jeff Jin, Gregory Barbosa, Trey Kell, Vamshi Punugoti, Edward Suh, Brett Smith, Andrew Futreal
Journal: Journal of Clinical Oncology (2016)

e23204 Background: MD Anderson Cancer Center seeks to leverage its considerable clinical and research enterprise by developing a Translational Research Accelerator (TRA) platform to integrate longitudinal clinical and research data. Over a 12-month period, TRA has yielded a methodological multi-step framework to implement a large-scale, extensible, secure and HIPAA-compliant information system. Methods: We identified 35 clinical and research domains. Owners of these data sources were contacted for establishing processes for collection of data into TRA under the auspices of an institutional strategy. Natural Language Processing (NLP) was applied on unstructured data (e.g. transcribed documents, clinical notes) to extract high-value clinical attributes. A framework for ensuring the security of data in TRA and compliance with research protocols was established. Data collection from source systems was initiated in a limited fashion to validate data flow processes. Data on 230,000 patients was initially loaded. Multiple visualization tools were configured. Many data collection issues were identified and resolved including infrastructure, data quality and permissions. A process for adding users to data access tools was developed and approved for security and compliance. TRA was introduced to a pilot group for feedback. Results: A proven methodology has been established to integrate subsequent data sources. TRA contains over 381,800,000 data points. Using feedback from a pilot group of researchers, 1000 high-value attributes were identified from a possible 1,660. We quickly identified key areas for improvement and additional datasets to integrate to support typical analyses i.e. survival curves, and curate reference datasets. Conclusions: The TRA is a new paradigm for data integration of longitudinal patient clinical and research data, purpose-built to accelerate research. After having successfully overcome some of these complexities to launch TRA we can point to a methodological framework that may inform similar initiatives at other institutions of some of the challenges and point to potential approaches for a way forward.
Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling
Authors: Laurel A. Grisanti, Toby P. Thomas, Rhonda L. Carter, Claudio de Lucia, Erhe Gao, Walter J. Koch, Jeffrey L. Benovic, Douglas G. Tilley
Journal: Theranostics (2018)

Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death.β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function.However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo.We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in vitro.Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo.Methods: Wild-type (WT) C57BL/6, β2AR knockout (KO), βarr1KO and βarr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function.Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s).Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a β2ARand βarr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time.Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner.RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on βarr-dependent β2AR signaling. Conclusion:Pepducin-based allosteric modulation of βarr-dependent β2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits.
Comparison of fluoropyrimidine based (FP)and taxane based platinum doublets (TP) in frontline treatment of patients with metastatic gastroesophageal adenocarcinomas (mGEAC): A retrospective analysis.
Authors: Hibah Ismail, AMR Mohamed, Yeohan Song, Nadine Abdallah, Malini Surapaneni, Seongho Kim, Kamgar Mandana, Jayadev Mettu, Alaa Akhras, Abdelrahman Ahmed, Philip Agop Philip, Anthony Frank Shields, Anteneh A. Tesfaye
Journal: Journal of Clinical Oncology (2017)

e15604 Background: Although, fluoropyrimidine (FP) and taxane based platinum doublet (TP) chemotherapy have demonstrated efficacy against advanced gastroesophageal cancer, these two regimens have not been compared in prospective trials. We retrospectively compared fluoropyrimidine based (FP)and taxane based platinum doublet (TP)chemotherapy in the frontline setting in patients with mGEAC. Methods: Patients with mGEAC treated at Karmanos Cancer Institute between 2000-2014 were reviewed. We compared progression free survival (PFS), Response rate (RR), and toxicity profile of the two regimens. Outcomes were analyzed using weighted estimates. Fisher’s exact tests and Kruskal-Wallis tests were used for categorical and continuous variables, respectively. Survival differences were assessed by a log-rank test. Results: Of the total136 patients, 39% (53) received FP and 61% (83) received TP chemotherapy. Males were 68% (94) of the patients. Gastric, esophageal and gastroesophageal adenocarcinomas contributed to 47% (64), 26.5% (36) and 26.5% (36) of the cases respectively. FOLFOX was the main regimen in FP (62%), followed by 5FU cisplatin (38%). Carboplatin paclitaxel was the main regimen in the TP group. There was no statistically significant difference between the FP and TP arms in terms of PFS, RR, and median OS. The estimated median PFS was 6.39 (95% CI, 5.54-11.15) for the FP group vs 6.92 months (95% CI, 6.13-9.02) for the TP group, (p = 0.90). Objective response rate was (48% for FP group Vs 56% for TP group, p = 0.70). There was more significant grade 4-5 toxicity in FP vs TP based regimen (79 % vs 55 % respectively, p = 0.004). Conclusions: The efficacy of fluoropyrimidine platinum doublet chemotherapy appears to be as comparable to taxane based platinum doublet in the frontline treatment of mGEC. However, the fluorpyrimidine based regimen appears to have more toxicity. Consideration of treatment adverse effects ought to be a key factor in determining the choice of either regimen in mGEAC.
An imaging/biology correlation study between radiomics features and anaplastic lymphoma kinase (ALK) mutational status in a uniform Chinese cohort of locally advanced lung adenocarcinomas.
Authors: Meilin Jiang, Pei Yang, Dennis Mackin, Hesham Elhalawani, Zijian Zhang, Wenying Peng, Yingrui Shi, Hui Wang, Hekun Jin, Abdallah Mohamed, Laurence Court, Clifton David Fuller, Lin Wu
Journal: Journal of Clinical Oncology (2018)

e20540 Background: Target therapy has shown proven survival benefit for patients with advanced non-small-cell lung cancer (NSCLC) with positive (+) anaplastic lymphoma kinase (ALK) gene rearrangement mutations. In the meantime, radiomics have been increasingly shown to be associated with pathological and biological correlates of NSCLC and its subsequent response to treatment. We hypothesize that radiomics features derived from baseline non-contrast-enhanced computed tomography (CECT) scans can serve as quantitative imaging biomarkers (QIBs) of ALK mutational status. Methods: Baseline non-CECT, as well as ALK molecular profiles for eligible patients, were retrospectively retrieved from a single institution. ALK testing was carried out using Fluorescence in situ hybridization. One radiographic lesion was contoured on each slice. CT scans along with STRUCT DICOM files were imported to an imaging analytics platform. 386 texture features from Shape, Gray level Cooccurence Matrix, Gray Level Run Length Matrix and Neighborhood Intensity Difference were extracted for each lesion. Boosted tree with eXtreme Gradient Boosting function was used to build a prediction model for ALK mutational status classification, with a subsequent 5-cross-fold-internal validation. Model performance was assessed based on the area under the curve (AUC) after plotting the Receiver Operating Characteristic (ROC) curve. Results: Out of 51 patients with known ALK status, 9 presented with (+) ALK as compared to 42 negative ALK patients. Upon performing the 10-cross-fold validation, this feature model showed an overall prediction accuracy of 80.39%, with a true positive rate of 46.15% in predicting ALK-Positive and 92.11% for ALK-Negative. The mean value of the area under the curve for the prediction model was 0.730.25. Conclusions: Radiomics features were correlated with the mutational status of ALK in Chinese adenocarcinoma NSCLC patients, which might provide more chance of personalizing therapy prescription, if associated with subsequent treatment response. Larger cohorts of similar patients are required to verify this hypothesis.
Safety and efficacy of trabectedin when administered in the inpatient vs. outpatient setting in a subset analysis of a phase III randomized clinical trial.
Authors: Robin Lewis Jones, Robert G Maki, Shreyaskumar Patel, George C. Wang, Chu Ri Shin, Roland Elmar Knoblauch, Trilok V. Parekh, Margaret von Mehren, George D. Demetri
Journal: Journal of Clinical Oncology (2017)

e22516 Background: Trabectedin (T) has been shown to improve progression free survival (PFS) (4.2 vs 1.5 months, HR 0.55, p &lt; 0.0001) in comparison to dacarbazine (D) in patients (pts) with advanced leiomyosarcoma or liposarcoma following failure of prior chemotherapy. Pts randomized to T in this phase III trial (ET743-SAR 3007) received T as a 24 hr IV infusion in either an inpatient (InP) or outpatient (OP) setting, based upon site preference. Here we report the safety, efficacy, and patient reported outcomes (PROs) of pts based on first infusion site of care. Methods: Pts were randomized 2:1 to receive T (1.5 mg/m 2 ) or D (1 g/m 2 over 20-120 min). Site of T infusion was based on institutional preference/standard of care. The site of T administration (InP vs OP) was collected for the first infusion with the assumption that site of care was unchanged for subsequent doses. Results: Of 378 pts treated with T, 100 (27%) and 277 (73%) pts received T as InP or OP, respectively. No differences were observed in PFS or overall survival (OS) by site of care (InP vs OP): Median PFS of 4.1 vs 4.2 months; HR 0.90, p = 0.49 and median OS of 14.3 vs 13.7 months; HR 0.89, p = 0.40. No difference in other efficacy endpoints between InP vs OP were observed: disease control rate (CR+PR+(SD≥18wks)) (38% vs 33%; Odds Ratio [OR] 1.22; p = 0.44) and Overall Response Rate (14% vs 8%; OR 1.76; p = 0.15)). Grade 3-4 adverse events (AEs) occurred in 87% InP vs 79% OP pts and grade 3-4 SAEs occurred in 43% InP vs 33% OP. The most common grade 3-4 AEs in both groups were increased ALT/AST, hematologic toxicity, nausea and fatigue. The incidence of grade 3-4 febrile neutropenia was similar in both groups at 5.0% InP vs 4.7% OP, as was increased blood creatine phosphokinase at 5.0% InP vs 6.1% OP, and catheter related complications of any grade at 16% InP vs 15% OP. No clinically meaningful differences were observed in PROs measured by MD Anderson Symptom Inventory scores. Conclusions: The majority of patients randomized to the trabectedin arm of the ET743-SAR-3007 Phase III study received trabectedin in the OP setting. Treatment outcomes with trabectedin suggest equivalent efficacy and safety when administered in the InP or OP setting. Clinical trial information: NCT01343277.
Outcome of 212 malignant phyllod tumor patients: A retrospective study from the French Sarcoma Group (GSF-GETO).
Authors: Mathias Neron, Christophe Sajous, Sophie Piperno Neumann, Camille Chakiba, Agnes Ducoulombier, Clémentine Owen, S Bastien Salas, Francois Bertucci, Esma Saada-Bouzid, Thibaud Valentin, Jacques-Olivier Bay, Emmanuelle Bompas, Nicolas Isambert, Aurélie Maran-Gonzalez, Carmen Llacer, Sebastien Carrère, Didier Cupissol, Simon Thezenas, Jean-Yves Blay, Nelly Firmin
Journal: Journal of Clinical Oncology (2017)

11055 Background: The optimal management of malignant phyllod tumors (MPT) is poorly documented. Objective:To study the characteristics and outcome of MPT patients (pts). Methods: Retrospective study from the nation-wide French sarcoma network (NetSarc) from 2000 to 2016. Inclusion criteria was central pathological review of MPT. End-points were local recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS). Results: 212 pts, from 13 centers, were included. Median age was 52.8 years (range: 16.8 - 90.5). All localized MPT pts (96.7%) underwent surgery with 41.4% of mastectomy. The median size was 5.8 cm (range: 1.5 - 30). R1/R2 resection was achieved in 40.1% pts (26.9% 1-2 mm margin, 12.2% 3-7 mm, 20.3% ≥8 mm), with 44.8% of second surgery (SS) for a final mastectomy rate of 72.6%. Presurgical biopsy was performed in 86.3% and associated with R0 resection ( p=0.044) and better LRFS ( p=0.012). Median follow-up was 4.1 years (range 0-14.8) and revealed 34 (16.6%), 48 (22.9%), 44 (20.8%) events for LRFS, MFS and OS, respectively. The 2-year OS rate was 89%. Prognostic factors found in multivariate analysis are presented in Table 1. Wider margins (≥8mm) were not associated with better outcomes. Adjuvant radiotherapy and chemotherapy were performed in 43.6% and 13.3% respectively and associated with longer LRFS, not significant in multivariate analysis. Conclusions: Mastectomy is associated with better local control, but not with MFS and OS. Age, tumor necrosis and metastatic disease are associated with poor prognosis in MPT pts. Our study suggests that margins of 3 mm are necessary and sufficient for the surgical management of MPT and emphasizes the importance of SS to obtain clear margins. [Table: see text]
TCT-389 Pre-Clinical Evaluation of a Novel Thin Strut (85 μm) Ultra-High Molecular Weight PLLA Sirolimus-Eluting Bioresorbable Scaffold: A Comparative Multi-Modality Imaging-Based Study
Authors: Marco Ferrone, Gilberto Melnick, Nicolas Isaza, Yanping Cheng, Jenn McGregor, Kamal Ramzipoor, Chang Lee, Gerard Conditt, Grzegorz Kaluza, Juan Granada
Journal: Journal of the American College of Cardiology (2018)
Uterine stem cells: from basic research to advanced cell therapies
Authors: Xavier Santamaria, Aymara Mas, Irene Cervelló, Hugh Taylor, Carlos Simon
Journal: Human Reproduction Update (2018)

Stem cell research in the endometrium and myometrium from animal models and humans has led to the identification of endometrial/myometrial stem cells and their niches. This basic knowledge is beginning to be translated to clinical use for incurable uterine pathologies. Additionally, the implication of bone marrow-derived stem cells (BMDSCs) in uterine physiology has opened the field for the exploration of an exogenous and autologous source of stem cells.In this review, we outline the progress of endometrial and myometrial stem/progenitor cells in both human and mouse models from their characterization to their clinical application, indicating roles in Asherman syndrome, atrophic endometrium and tissue engineering, among others.A comprehensive search of PubMed and Google Scholar up to December 2017 was conducted to identify peer-reviewed literature related to the contribution of bone marrow, endometrial and myometrial stem cells to potential physiological regeneration as well as their implications in pathologies of the human uterus.The discovery and main characteristics of stem cells in the murine and human endometrium and myometrium are presented together with the relevance of their niches and cross-regulation. The current state of advanced stem cell therapy using BMDSCs in the treatment of Asherman syndrome and atrophic endometrium is analyzed. In the myometrium, the understanding of genetic and epigenetic defects that result in the development of tumor-initiating cells in the myometrial stem niche and thus contribute to the growth of uterine leiomyoma is also presented. Finally, recent advances in tissue engineering based on the creation of novel three-dimensional scaffolds or decellularisation open up new perspectives for the field of uterine transplantation.More than a decade after their discovery, the knowledge of uterine stem cells and their niches is crystalising into novel therapeutic approaches aiming to treat with cells those conditions that cannot be cured with drugs, particularly the currently incurable uterine pathologies. Additional work and improvements are needed, but the basis has been formed for this therapeutic application of uterine cells.
Letter by Aloia Regarding Article, “Derivation and Validation of a Novel Right-Sided Heart Failure Model After Implantation of Continuous Flow Left Ventricular Assist Devices: The EUROMACS (European Registry for Patients with Mechanical Circulatory Support) Right-Sided Heart Failure Risk Score”
Authors: Elio Aloia
Journal: Circulation (2018)

I would like to start by thanking the authors of this article 1 for its great quality.Acute right ventricular failure after left ventricular assist device implantation causes systemic congestion, altered drug metabolism, malnutrition, diuretic resistance, and poor quality of life.It may lead to impaired left ventricular assist device flow, difficulty in weaning from cardiopulmonary bypass, decreased tissue perfusion, and multiorgan failure. 2 Understanding right ventricular failure is important because it is associated with increased perioperative mortality, prolonged hospitalization, and worse survival odds even after cardiac transplantation. 3ow, for the first time, 1 thanks to the authors, we can draw information from a stratified and randomized population that used the same generation of devices.In fact, reviewing the literature 2 about right ventricular failure after left ventricular assist device implantation, I found a lot of limitations and heterogeneities in terms of the following:1. Definition of right ventricular failure 2. Careful and precise selection criteria 3. Lack of stratification for Intermacs classes 4. Lack of stratification for the cause of heart failure 5. Presence of devices belonging to different generations Certainly, many questions rise about mechanical circulatory support: first of all, the implantation's timing, because treating patients with severe and compromised organ function is associated with poor outcomes; therefore, starting this therapy too early may not be beneficial or cost-effective.Furthermore, the need for an right ventricular assist device is associated with worse outcomes, 4 but elective right ventricular assist device correlates with better long-term survival than an emergency implantation. 5ence, after we got a novel right-sided heart failure model after implantation of continuous flow left ventricular assist devices, 1 I hope we will soon have another good score to predict the need of a right ventricular assist device, before the implantation, to better schedule biventricular assist device implantation rather than using it only in terms of rescue therapy.
Prognostic role of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in metastatic breast cancer (MBC) patients: First clues for cost-effective biomarkers.
Authors: Giacomo Pelizzari, Lorenzo Gerratana, Debora Basile, Maria Grazia Vitale, Michele Bartoletti, Camilla Lisanti, Valentina Fanotto, Alessia Liguori, Marika Cinausero, Claudia Bozza, Elena Poletto, Gaetano Pascoletti, Stefania Russo, Claudia Andreetta, Marta Bonotto, Mauro Mansutti, Alessandro Marco Minisini, Francesco Curcio, Gianpiero Fasola, Fabio Puglisi
Journal: Journal of Clinical Oncology (2018)

e13079 Background: Elevated ALP and LDH levels have been associated with worse prognosis in several malignancies; however, their role in MBC remains unclear. We aim to explore the prognostic impact of ALP and LDH levels at baseline and after 12 weeks of first line therapy in MBC patients (pts). Methods: This retrospective study analyzed 396 consecutive pts with a diagnosis of MBC, treated between 2007 and 2017 at the Oncology Department of Udine (Italy). The prognostic impact of elevated baseline ALP ( > 104 U/L) and LDH ( > 480 U/L), and their changes after 12 weeks of first line treatment were investigated through Cox regression. Results: After a median follow-up of 52.8 months, median overall survival (OS) was 30.9 months and median progression free survival (PFS) was 9.2 months. Pts with baseline elevated ALP or LDH were 33.8% (126/373) and 31.5% (70/222), respectively. The 16.9% (37/219) of pts had both elevated ALP and LDH. By univariate analysis, pts with baseline elevated levels of ALP (HR 1.82, 95% CI: 1.39–2.38, p < .0001), LDH (HR 2.27, 95% CI: 1.58–3.24, p < .0001) or both (HR 3.36, 95% CI: 2.15–5.27, p < .0001; vs pts with normal ALP and LDH) had worse OS. By multivariate analysis, after adjustment for molecular profiles, performance status (PS), number of sites, central nervous system (CNS), liver, and bone involvement, a worse prognosis was confirmed for pts with high baseline levels of LDH (HR 1.74, 95% CI: 1.12–2.69, p = .013) and elevated levels of both ALP and LDH (HR 2.84, 95% CI: 1.64–4.91, p < .0001; vs pts with normal ALP and LDH). When considering ALP and LDH levels after 12 weeks of first line treatment, by multivariate analysis, pts with stably elevated LDH had worse OS (HR 2.61, 95% CI: 1.15–5.9, p = .021) and PFS (HR 2.88, 95% CI: 1.40–5.89, p = .004) compared to pts with stably normal LDH. Conclusions: High pre-treatment levels of LDH or both ALP and LDH or stably high LDH levels during first line treatment are negative and independent prognostic factors also when adjusted for liver and bone localizations. The present study paves the way to a prospective validation of ALP, LDH and their combination as promising cost-effective biomarkers.