tbuckley/cabot-search huggingface dataset:
Trastuzumab emtansine (T-DM1) and ribociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 (CDK 4/6), for patients with metastatic HER2-positive breast cancer.
Authors: Laura Spring, Shom Goel, Sara Sutherland, Jeffrey G. Supko, Dejan Juric, Steven J. Isakoff, Erica L. Mayer, Beverly Moy, Sara M. Tolaney, Aditya Bardia
Journal: Journal of Clinical Oncology (2019)

1028 Background: Current therapeutic efforts in the management of HER2+ MBC focus on targeting the HER receptor family, however co-inhibition of targets downstream of the HER2 pathway, such as cyclin D-CDK 4/6, could enhance therapeutic efficacy. We conducted a phase 1b study of the CDK4/6 inhibitor ribociclib and T-DM1 in patients (pts) with HER2+ MBC. The primary objective was to determine the recommended phase 2 dose (RP2D) of ribociclib plus T-DM1. Secondary objectives included safety, PK assessments, and efficacy. Methods: Pts with HER2+ MBC who previously received at least 1 taxane and trastuzumab-containing regimen in any setting were eligible. Pts with previous CDK4/6 inhibitor exposure, QTcF &gt; 450msec, or unstable brain metastases were excluded. Ribociclib was given orally for 2 weeks of a 21-day cycle (days 8-21), with T-DM1 given at 3.6 mg/kg every 3 weeks on day 1. A standard 3+3 dose escalation design was used to evaluate various doses of ribociclib in combination with T-DM1 to determine the RP2D. Results: From 5/2016 – 10/2018, 10 pts (8/10 ER+) were enrolled with a median age of 53 (38-72) and median of 1 (0-2) prior therapies for MBC. During dose-escalation, pts received doses of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 1). No DLTs were observed. The most common treatment related grade 3 or higher AEs were neutropenia (50%), infection (20%), anemia (10%), and thrombocytopenia (10%). 4/10 pts had dose reductions due to toxicity. The average concentration of ribociclib at steady state was similar at each dose level, ranging from 273 to 413 ng/mL. Among 9 evaluable pts, the ORR was 33% (3/9) and the other 6 pts had stable disease. After a median follow-up time of 10.9 months, the median PFS was 12.5 months (95% CI [10.5. 20.9]). Biomarker results will be presented at the meeting. Conclusions: Co-targeting HER2 and CDK4/6 with the combination of ribociclib with T-DM1 was well tolerated with evidence of clinical activity. Based on PK analysis and dose reductions, 400 mg is the RP2D. Further evaluation is warranted for patients with HER2+ MBC. Clinical trial information: NCT02657343.
Association of proton pump inhibitors with fracture risk in patients with rheumatoid arthritis
Authors: Toshihiro Sugiyama
Journal: Annals of the Rheumatic Diseases (2019)

Association of proton pump inhibitors with fracture risk in patients with rheumatoid arthritisIn a recent longitudinal prospective observational study that included more than 10 000 adult patients with rheumatoid arthritis (RA) who had no prior fracture, Ozen and colleagues 1 confirmed that proton pump inhibitors (PPIs) were frequently prescribed (approximately 30% of the participants) and showed no association between PPI use and fracture risk; the adjusted HR and 95% CI were 0.92 and 0.80 to 1.06, respectively.This seems to be a timely and clinically meaningful finding.I agree with the authors 1 that higher use of bisphosphonates among the participants with PPI use influenced the aforementioned association.After treatment with bisphosphonates, however, reduction in vertebral fracture risk is obviously larger than that in non-vertebral fracture risk; for example, the latest clinical practice guideline 2 described that HR (95% CI) of alendronate was 0.56 (0.46 to 0.67) in vertebral fracture risk and 0.83 (0.74 to 0.93) in non-vertebral fracture risk.Accordingly, the involvement of bisphosphonates is limited, because HR (95% CI) of PPIs was 1.04 (0.85 to 1.27) in vertebral fracture risk and 0.82 (0.69 to 1.00) in non-vertebral fracture risk. 1 Here I would like to suggest that accumulating evidence 1 3-6 is unlikely to support a causal relationship between PPI use and fracture risk, regardless of RA, and thus the frequently used drug would not be a modifiable risk factor for fractures, although it is important to note that risk of fractures as well as falls could be higher among many patients with PPI use 6 as shown by the unadjusted HR 1.36 (95% CI 1.19 to 1.55).
Association of TGF-β expression with intratumoral infiltration of cytotoxic T lymphocytes in patients with microsatellite-stable colorectal cancer.
Authors: Amir Mehrvarz Sarshekeh, Riham Katkhuda, Anuj Verma, Shailesh M Advani, Michael J. Overman, Dipen M. Maru, Scott Kopetz
Journal: Journal of Clinical Oncology (2019)

3577 Background: Transforming growth factor- β pathway (TGF-β) has an established role in promoting growth, invasion, metastasis as well as epithelial to mesenchymal (EMT) transition. Among 4 different described molecular subtypes of colorectal cancer (CRC), consensus molecular subtype 4 (CMS4) comprises up to 25% of CRC pts, distinguished by activation of this pathway, and is associated with higher relapse rate and poor prognosis. Recently, it has also been proposed that TGF-β activation drives immune evasion in murine models, but these findings have not been clinically validated. Methods: Using multi-gene RNA expression profiling, fresh-frozen paraffin-embedded samples of 35 patients with CRC were analyzed to determine TGF-β and EMT expression levels. Multiplexed IHC staining was performed on FFPE tumor blocks by using the Opal 7-Color fIHC Kit and the stained slides were scanned by a Vectra multispectral microscope (PerkinElmer) to measure infiltration of immune cells (i.e., T lymphocytes, cytotoxic T lymphocytes (CTL), T cell antigen-experienced, macrophages, etc.) in the tumor, stroma, and both components. TGF-β and EMT expression levels – as continuous variables - were compared with the infiltration of various immune cells using Spearman’s rank correlation analysis. Results: Among 35 pts, 28 pts had non-CMS1/MSS CRC. TGF-β RNA expression in the tumor microenvironment of these samples was inversely associated with the infiltration of CTL into the tumor (r=-0.43, p= 0.022). In contrast, there was no association of TGF-β with non-cytotoxic T-cells or macrophage infiltration. The tumor and stromal CTL infiltration differed substantially by CMS ( p=0.04, p=0.02, respectively) with tumor infiltration lowest in CMS4 (n=7). Consistent with this, EMT gene signature, which includes TGF-β expression, showed a similar inverse correlation with CTL infiltration (r=-0.48, p=0.009). Conclusions: TGF-β and EMT gene signatures have important roles in the exclusion of CTL in the tumor microenvironment of CRC pts. Inhibiting TGF-β pathway can potentially increase the intratumoral infiltration of CTL, which is a necessary (but not sufficient) step for immunotherapy response in MSS CRC. Clinical trials evaluating this hypothesis are currently ongoing (NCT03436563).
External validation of a prognostic model for overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Susan Halabi, Sandipan Dutta, John C. Araujo, Christopher Logothetis, Cora N. Sternberg, Andrew J. Armstrong, Michael Anthony Carducci, Kim N. Chi, Johann S. De Bono, Daniel Peter Petrylak, Karim Fizazi, Celestia S. Higano, Eric Jay Small, William Kevin Kelly
Journal: Journal of Clinical Oncology (2019)

5022 Background: We have previously developed and externally validated a prognostic model of OS in men with mCRPC treated with docetaxel (D), which included eight predictors: opioid analgesic use, ECOG performance status, albumin, disease site, LDH, hemoglobin, PSA, and alkaline phosphatase. We have used this model to develop prognostic risk groups. We sought to externally validate this model in a broader group of men with mCRPC and in specific subgroups (White, Black, Asian patients, different age groups) and to validate the two and three prognostic risk groups in this large dataset. Methods: Data from 5,790 mCRPC men randomized on 5 phase III trials were utilized to validate the prognostic model of OS: D +/- zibotentan (ENTHUSE), D +/- lenalidomide (MAINSAIL), D +/- dasatinib (READY), D+/- custirsen (SYNERGY), and tasquinimod/placebo)). We applied the estimated parameters from the prognostic model to each of the five data sets and computed a risk score. We assessed the predictive performance of the model by computing the time-dependent area under the receiver operating characteristic curve (tAUC) and validated the two-risk (low, high) and three-risk prognostic risk groups (low, intermediate, high) that were defined by the model. Results: The tAUC for the different groups is presented in the table. Race, age, and treatment subsets had similar results. For the two prognostic risk groups, the median OS in the low and high groups were 27.6 months (95% CI = 26.6-28.7) and 13.8 months (95% CI = 13.3-14.4). For the three prognostic risk group, median OS in the low, intermediate and high groups were 29.7 months (95% CI = 28.3-31.4), 19.0 month (95% CI = 18.3-20.4) and 12.1 months (95% CI = 11.5-12.9), respectively. Conclusions: This prognostic model for OS in men with mCRPC has been validated in a larger dataset, yields similar results across race, age and treatment groups. The model is robust and can be used to identify prognostic risk groups of patients for stratification and enrichment trials. Clinical trial information: NCT00626548. [Table: see text]
Validation and utilization of NGS based HEMEaccuTest panel and analysis software for hematological malignancies.
Authors: Hyun-Jeung Choi, In-seon Lee, Min Kyoung Lee, Ji-Eun Im, Kyongyong Jung, Keunsook Kathy Lee, YoungJoon Moon, Kwang Joong Kim
Journal: Journal of Clinical Oncology (2019)

e14606 Background: Hematological malignancies are forms of cancer that originate in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Hematological malignancies can be classified as leukemias, lymphomas, multiple myeloma (MM), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) based on the cell type where they originate. Detection of genetic alteration in hematological malignancies is increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is an advanced technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related for clinical diagnostics. Methods: We developed the targeted NGS panel, HEMEaccuTest and automatic analysis software, NGeneAnalySys for estimating the relative pathogenicity of hematological malignancies. HEMEaccuTest covers about the 310 kilobases with exon regions of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. the diagnostic utility of the panel and software were validated using genotype-known reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600x and a minimum coverage depth of 100x. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity and specificity of the panel were high in a comparison to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by an excellent simulating algorithm of NGeneAnalySys. Conclusions: This analytical validation demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent tool for disease definition and therapeutic strategy in hematological malignancies.
MR and PET-CT monitoring of tissue-engineered vascular grafts in the ovine carotid artery
Authors: Frederic Wolf, Vera Paefgen, Oliver Winz, Marianne Mertens, Sabine Koch, Nicolas Gross-Weege, Agnieszka Morgenroth, Anne Rix, Heike Schnoering, Khaled Chalabi, Stefan Jockenhoevel, Twan Lammers, Felix Mottaghy, Fabian Kiessling, Petra Mela
Journal: Biomaterials (2019)
Analysis of age, tumor-sidedness, and mismatch repair (MMR) genes with response to immune checkpoint inhibitors (ICIs) in MMR-deficient (dMMR) colorectal cancer (CRC) patients (pts): A multi-institutional study.
Authors: Ibrahim Halil Sahin, Wanqi Chen, Mohamad Bassam Sonbol, Satya Das, Zhengjia Chen, Mehmet Akce, Olatunji B. Alese, Walid Labib Shaib, Daniel H. Ahn, Kristen Keon Ciombor, Mitesh J. Borad, Jordan Berlin, Tanios S. Bekaii-Saab, Amber Draper, Bassel F. El-Rayes, Christina Wu
Journal: Journal of Clinical Oncology (2019)

e15029 Background: ICIs induce durable responses in dMMR CRC pts with overall response rates (ORR) of 30-50%. Even though the loss of expression of any MMR gene predicts ICIs response, it is unknown if ORRs are similar across all MMR genes (MLH1, PMS2, MSH2, and MSH6). In this study, we analyzed the impact of each specific MMR gene loss and clinical characteristics of pts with best response to ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or microsatellite instability-high (MSI-H) by PCR, and received ICIs between 01/01/2012 and 10/01/2018 at Winship Cancer Institute of Emory University, Mayo Clinic or Vanderbilt University Medical Center. Due to the pattern of frequent concurrent loss and functional dependency, the groups were categorized as MLH1 ±PMS2 vs. MSH2 ±MSH6. Cox proportional hazard model and Fisher’s exact test were used for the best response and the distribution of variable among the subgroups. Results: A total of 45 pts with dMMR CRC were identified. ORRs in MLH1 ±PMS2 and MSH2 ±MSH6 groups were 68% and 57.1% respectively without statistical difference (Table). Pts with age &lt; 50 and 50-65 years old had better ORRs compared to pts with age &gt;65 (58.3%, 85.7% and 42.1% respectively, P=0.036). Left-sided tumors had a trend toward higher ORRs compared to right-sided tumors (83.3% vs 51.5% P=0.086). Gender and BRAF status were not predictors of response. BRAF mutations were more common in right-sided tumors (29.6% vs 11.1% respectively) and in older patients. Conclusions: Our data suggest that MSI-H CRC pts aged 50-65 treated with ICIs, have improved ORR compared to pts &gt; 65; pts with left-sided tumors have a trend toward improved ORR compared to those with right sided tumors. [Table: see text]
Abstract P031: Correlation of Sibling Lipid Levels From a Statewide Child Cardiac Risk Factor Registry
Authors: Lee A Pyles, Christa Lilly, William A Neal
Journal: Circulation (2016)

Introduction: Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) is a project that has assessed childhood risk factors for cardiovascular disease (CVD) for nearly twenty years. We have screened approximately 95,000 children from WV that now include 60,403 with lipid panels. Eight-thousand-five-hundred-fifty-seven persons have one or more siblings who have participated in the project. To begin to consider genetic primordial antecedents of CVD in WV schoolchildren, we linked sibships for analysis. Methods: Linkage software designed to deduplicate EHRs proved poorly adaptable to the problem of family matching. Successive excel spreadsheets were used to directly match either mother or father’s first and last name with care taken to avoid similar names by requiring additional matching parameters. A group of children were identified with younger siblings subsequently enrolled in CARDIAC and the two older children were matched for analysis when 3 siblings were found. Body Mass Index z-score was calculated for each child. Fasting lipid levels were obtained by venipuncture and measured by a commercial laboratory (LabCorp). Results: Children (5259)with at least one sibling with LDL levels available for both were found along with 1384 third siblings. The mean LDL level for the first child was 90.5 mg/dl and 92.1 mg/dl for the second child. The mean BMI z-score was +0.83 for the group of 95,000 children, +0.73 for the first sibling and +0.72 for the second sibling. Sibling BMI z-scores were strongly correlated. Multivariate analysis demonstrated that the LDL level for the second child correlated strongly with both the older sibling’s LDL level and with the second child’s BMI z-score. This model showed R2 = 0.15 and the following prediction equation: LDLsibling2 = 56.3 + 0.377*LDL-proband + 2.24*BMI-z-score-sibling2 p = 4.33 x 10 -175 for LDL and p = 4.06 x 10 -15 for BMI z-score Six-hundred-sixty-eight children had an LDL level greater than 130 mg/dl including 88 sets of siblings. 12 pairs of siblings each had an LDL level &gt; 160 mg/dl. Conclusion: the analysis demonstrates a strong correlation between sibling LDL-c levels that is not as well explained by the correlation of BMI z-score as by LDL-c. This analysis along with our recent study of LDL and height will help to characterize CVD risk in this population to focus future investigations in children and families.
Metformin, aspirin and statin and risk of cancer: A population-based study in Thailand.
Authors: Songporn Oranratnachai, Piyaporn Phetchoo, Sasivimol Rattanasiri, Ammarin Thakkinstian, Somthawin Lukerak, Prin Vathesatogkit, Piyamitr Sritara, Ekaphop Sirachainan, Thanyanan Reungwetwatttana
Journal: Journal of Clinical Oncology (2019)

e13095 Background: : There were the conflicted results of the association of ASA, metformin or statin and risk of cancer in the previous studies. This is a population-based study in Thai population which aims to investigate the association between these drugs and the risk of cancer. Methods: A population-based retrospective study was done in Electricity Generating Authority of Thailand (EGAT) 1 and 2 databases which have been contained the 27-year and 15-year follow-up time, respectively. This database composed of the clinical characteristics, onset of cancer, and history of interested drugs from the questionnaire, together with the laboratory result from January 2002 to December 2015. We adjusted for age, sex, BMI, smoking and alcohol consumption. The incidence rate ratio (IRR) was estimated for the association between incidence of cancer and interested drugs. Results: Among 2508 and 2731 participants in EGAT1 and 2 respectively, the incidence of cancer was 8.3% in EGAT 1 and 3.5% in EGAT 2. From univariate analysis, use of interested drugs was significant associated with increased risk of cancer with IRR 1.74 ( P&lt; 0.001) for ASA, IRR 1.54 ( P= 0.043) for metformin and IRR 1.64 ( P= 0.001) for statin. In multivariate analysis, only ASA showed significant increasing risk of cancer with IRR 1.47 ( P= 0.021). There was a trend increasing risk of cancer for metformin and statin users but not significant. Older age, low BMI, and female significantly associated with higher risk of cancer. In sub-group analysis, age and alcohol were significantly increased risk of GI cancer, while ASA use showed a non-significant trend of increasing risk of GI cancer. HBV infection was a strongly risk factor for hepatobiliary cancer and statin use had a trend lowering risk of this cancer but it was not statistically significant. Metformin also showed a non-significant trend of increasing risk of thoracic cancer. Conclusions: ASA use significantly associated with increasing risk of cancer but metformin and statin showed a trend of higher risk of cancer. These drugs may associate with cancer metabolome pathway which maybe an important role of carcinogenesis. However, ASA, metformin or statin use and risk of cancer is needed to confirm in the longer follow-up and larger cohort.
A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate
Authors: Wenshan Wang, Jeff Ishibashi, Sophie Trefely, Mengle Shao, Alexis J. Cowan, Alexander Sakers, Hee-Woong Lim, Sean O’Connor, Mary T. Doan, Paul Cohen, Joseph A. Baur, M. Todd King, Richard L. Veech, Kyoung-Jae Won, Joshua D. Rabinowitz, Nathaniel W. Snyder, Rana K. Gupta, Patrick Seale
Journal: Cell Metabolism (2019)
Evolution of the myeloid-derived suppressor cells in advanced breast cancer and comparative analysis with a healthy population cohort.
Authors: Natalia Palazón-Carrión, Carlos Jiménez-Cortegana, Esther Holgado, Josefina Cruz Jurado, Jose Luis Alonso Romero, María Luisa Sánchez Leon, Victor Sanchez Margalet, Esteban Nogales, Fernando Moreno Anton, Vanesa Quiroga Garcia, Raquel Andres, Marta Santisteban, Javier Cortes, Luz Milva Rodríguez-Rodríguez, Asuncion Soto Gutierrez, Mana Gion Cortes, A. Nieto Garcia, Massimo Chiesa, Susana Bezares, Luis De la Cruz-Merino
Journal: Journal of Clinical Oncology (2019)

2543 Background: High levels of myeloid-derived suppressor cells (MDSCs) seem a negative prognostic factor in advanced breast cancer (ABC) patients (pts). Preclinical studies suggest an immunomodulatory effect of some classical anti-tumor agents through alteration of MDSCs homeostasis. We analyzed the association of MDSCs and clinical evolution of ABC pts, taking into account the systemic treatment (tx) modulation of MDSCs levels in pts from two studies (“A”: GEICAM/2015-04 PANGEA-BREAST, NCT03025880 “Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC”, and “B”: PI-0502-2014 “Peripheral blood analyses of immune response induced by 1 st line tx of ABC according to clinical guidelines”). Methods: MDSCs (CD33+ CD11b+) levels were determined by flow-cytometry in peripheral blood samples at three time points (basal, at cycles 3 and 6) from: 39 HER2-negative heavily pretreated pts from study “A”, 43 non-pretreated pts (all subtypes) from study “B” and 20 women from a healthy cohort (HC), with no cancer diagnosis. MDSCs levels from the different cohorts were compared and correlated with pts with Clinical Benefit (CB: partial/complete response + disease stabilization) vs pts with Progressive Disease (PD). Results: Tx response was assessed in 33 pts (85%) from study “A” and 39 pts (91%) from study “B”. CB was observed in 11 pts (28%) from study “A” and in 34 (79%) from study “B” while PD was observed in 22 pts (56%) from study “A” and in 5 (12%) from study “B”. Basal MDSCs levels were significantly higher in ABC pts (studies “A”+”B”) than in HC (15.95 vs 0.81 cells/µl, p = 0.009). At cycle 6, MDSCs were considerably lower in pts with CB vs DP (2.90 vs 13.75 cells/µl, p &lt; 0.001). This decrease was more pronounced in study “B” than in study “A” pts (p &lt; 0.001 vs p = 0.074, respectively), probably due to differences in number of events, tumor subtypes and tx between both studies. Conclusions: Our results suggest that ABC pts show alterations in MDSCs and that their decrease along tx may have a positive predictive value, highlighting the importance that immune-competent status may play in the evolution of ABC. MDSCs may represent a target for therapeutic purposes in ABC.