tbuckley/cabot-search huggingface dataset:
The first report of multicenter validation study on curebest 95GC breast, a multi-gene assay to predict prognosis of node negative and ER positive breast cancer patients.
Authors: Ken-ichi Ito, Takaaki Oba, Kenjiro Aogi, Shozo Ohsumi, Mina Takahashi, Noriyuki Shiroma, Miyo Oda, Koji Arihiro, Fumine Tsukamoto, Sho Shiino, Masayuki Yoshida, Kazuki Kishi, Takayuki Kinoshita
Journal: Journal of Clinical Oncology (2017)

e12107 Background: Curebest™ 95GC Breast (95GC) is one of the multi-gene assays to predict prognosis of node negative and estrogen receptor (ER) - positive breast cancer patients, developed using 95 gene-set without overlap with that used in Oncotype DX Ⓡ (ref 1). It has been shown to have the capability to classify the “intermediate” patients determined using Recurrence Online (microarray-based simulation model for Oncotype DX Ⓡ ) but was validated only using the data from single institute and public database. Here we report the result of the first multi-center validation study for this multi-gene assay. Methods: ER-positive and T1-2/N0/M0 breast cancer patients who received adjuvant hormonal therapy were enrolled retrospectively. Fresh frozen tissues were applied to the assay, resulting classification into “L” and “H”, which was used for the validation on 5 year recurrence free survival (5Y-RFS) data of each patient. Results: 73 cases out of 150 enrolled cases were eligible and analyzed. 46 patients were classified as “L” whose 5Y-RFS was 96.5% (95%CI:89.5-98.9) while 27 patients were classified as “H” whose 5Y-RFS was 79.0% (95%CI:63.6-88.5). There was a statistically significant difference between RFS of “L” and “H” group by Log-Rank test (p = 0.0016). Significant association with 95GC were seen in histological grade (p = 0.0012), Recurrence Online (p &lt; 0.001) and PAM50 (p &lt; 0.001). The assay could classify the patients of histological grade 2, intermediate group by Recurrence Online (RS &gt; 17, RS &lt; 31) and Luminal B patients into “L” and “H”. Conclusions: Curebest™ 95GC Breast was well validated by this first multi-centered retrospective study on 5Y-RFS of the ER positive, node-negative patients who received only hormonal therapy in adjuvant setting. This result indicates the usefulness of 95GC as a novel multi-gene assay, as it can classify target patients into 2 groups, “H” and “L” according to predicted prognosis of 5Y-RFS. Reference: 1. Naoi et al. Breast Cancer Res Treat (2011) 128:632-641
Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease
Authors: Linda Xiaoyan Li, Lucy X. Fan, Julie Xia Zhou, Jared J. Grantham, James P. Calvet, Julien Sage, Xiaogang Li
Journal: Journal of Clinical Investigation (2017)

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 double-knockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early- and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.
Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from <scp>BIOSTAT‐CHF</scp>
Authors: João Pedro Ferreira, Patrick Rossignol, Jean‐Loup Machu, Abhinav Sharma, Nicolas Girerd, Stefan D. Anker, John G. Cleland, Kenneth Dickstein, Gerasimos Filippatos, Hans L. Hillege, Chim C. Lang, Jozine M. ter Maaten, Marco Metra, Leong Ng, Piotr Ponikowski, Nilesh J. Samani, Dirk J. van Veldhuisen, Aeilko H. Zwinderman, Adriaan Voors, Faiez Zannad
Journal: European Journal of Heart Failure (2017)
Use of skin biomarker profiles to distinguish Schnitzler syndrome from chronic spontaneous urticaria: results of a pilot study
Authors: H. Bonnekoh, J. Scheffel, M. Maurer, K. Krause
Journal: British Journal of Dermatology (2017)

urticarial rash is a hallmark symptom of systemic autoinflammatory diseases such as Schnitzler's syndrome (SchS). Clinically, the urticarial rash cannot be distinguished from wheals in chronic spontaneous urticaria (CSU). Thus, it is commonly misdiagnosed as CSU.1 SchS is characterized by monoclonal gammopathy, long-term complications including the development of lymphoma, and systemic inflammation.

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Inter-laboratory evaluation of a novel DEPArray-HER2 FISH assay.
Authors: Amanda Gerber, Lisa Koenig, Lori Millner, Lindsay Strotman, Valeria Sero, Nicolò Manaresi, Sabine Kasimir-Bauer, Farideh Z. Bischoff
Journal: Journal of Clinical Oncology (2017)

e12506 Background: Fluorescent in Situ Hybridization (FISH) is a method currently used for detection and assessment of HER2 gene amplification. Although clinical guidelines set forth by CAP/ASCO exist to ensure accuracy, limitations in HER2test results due to sample preparation, assay-conditions and tumor heterogeneity remain unresolved. We have successfully demonstrated analytical confidence in performing HER2 FISH on DEPArray™ sorted and recovered tumor cells. In this study, we aimed to evaluate inter-laboratory concordance of the DEPArray™ HER2-FISH assay. Methods: Three laboratories equipped with the DEPArray™ were designated as testing sites for this study. Positive control SKBr3 cells embedded in paraffin as well as 20 invasive breast carcinoma FFPE samples were blinded and evaluated by each of the three labs. Control and patient samples were processed through the DEPArray™ beginning with dissociation of the FFPE curls followed by single-cell image-based cell sorting to separate and recover pure distinct tumor cell populations prior to HER2 FISH analysis. Data was only obtained when ∼200 intact cytokeratin+/vimentin-/DAPI+ tumor cells from each sample were recovered and used for subsequent FISH using a standard dual-color HER2/CEP17 FISH procedure. Results: Overall, 80% concordance between DEPArray™-HER2 and conventional HER2 (6 HER2 negative and 10 HER2 positive) was observed between lab(s) and the conventional HER2 method. In each of 4 cases, a discordant HER2 result was reported by one of three sites. In three of these discordant cases, the DEPArray™ HER2 ratio was reported as amplified while the conventional result was negative. In the remaining discordant case, the converse was observed by one site; however, this case was initially evaluated 15 years ago. All three sites correctly scored the SKBr3 positive control cells. Conclusions: The results showed a high concordance rate of correct HER2 status classification. This data further supports the understanding that tissue heterogeneity can indeed give rise to discordant results that may consequently affect treatment options for patients. We demonstrate that sample preparation by DEPArray™ may aid in a more precise classification for tumor biomarker status.
Homogeneity of variance of measures associated with objective assessment of esthetic outcome after treatment with radiation therapy in early breast cancer.
Authors: Norman R. Williams
Journal: Journal of Clinical Oncology (2017)

e12085 Background: Breast cancer is an increasingly treatable disease which means that many women will live a long time with the esthetic consequences of their treatment. The majority of women with early breast cancer are given whole breast external beam radiation therapy (EBRT) after lumpectomy (breast conservation). It has been demonstrated, using an objective assessment of esthetic outcome in patients from a randomized trial that “redness”, a surrogate for radiation induced erythema grade I or II, is significantly greater after one year in patients receiving EBRT compared with those receiving intraoperative radiation therapy (IORT). However, it has been observed that not all women given EBRT have detectable erythema, which implies that there is a greater variability in this group. In order to test this hypothesis a test of unequal group variances was performed. Methods: 991 frontal digital photographs were analyzed from women participating in the TARGIT A Trial (NCT00983684) at four sites (Lublin, Mannheim, Copenhagen and Perth). Photographs taken at baseline (before surgery), 1 and 2 years (after surgery and EBRT or IORT) were objectively assessed, blinded to treatment received, by BCCT.core software which produces overall Harris scores, and scores for various measures of symmetry, color and scar. The scores for color were analyzed in SAS v9.4 using PROC GLM. Results: cEMDL, a color score associated with "lightness", showed significant heterogeneity of variance (using Levene's and Welch's Tests, p &lt; 0.0001) in the women treated with EBRT, but not in those treated with IORT (p = 0.4). However, cX2b (associated with "redness") showed significant heterogeneity of variance in both the EBRT and IORT treated groups (p &lt; 0.0001), although the point estimates moved in different directions. Conclusions: This study demonstrates that there are complex changes in skin color following radiation therapy to the breast, and assumptions regarding homogeneity of variance should be checked if required by the statistical analysis.
Abstract NTOC-117: CD73 BLOCKADE OVERCOMES RESISTANCE TO AGONISTIC ANTI-CD137 ANTIBODY THERAPY IN OVARIAN CANCER
Authors: Siqi Chen, Jie Fan, Donye Dominguez, Qin Lei, Alan Long, Deyu Fang, Bin Zhang
Journal: Clinical Cancer Research (2017)

Abstract Agonist antibodies (Ab) directed against costimulatory molecule CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes are currently in various stages of pre-clinical and clinical development in advanced ovarian cancers, though therapeutic benefit has been limited as single agents. Here, we identified a novel mechanism of tumor-reactive CD8+ T cell unresponsiveness in ovarian cancer driven by the upregulation of CD73 (ecto-5′-nucleotidase), which prevents CD8+ T cell activity from engagement of the CD137 costimulatory molecule. Accordingly, CD73-deificient mice treated with anti-CD137 Ab survived significantly longer wild-type mice against an ovarian tumor challenge. To explore the therapeutic relevance of these observations, we combined anti-CD137 and anti-CD73 Ab to treat mice with established ovarian cancers. This combination therapy induced tumor regression associated with enhanced antitumor CD8+ T cell responses and reduced CD4+Foxp3+ regulatory T cells number and function. Mechanistically, CD137 engagement-triggered antitumor T cell activity was diminished in response to microenvironmental transforming growth factor-β (TGF-β) that was essential for CD73 induction. Furthermore, extracellular adenosine generation by CD73 abrogated T cell activity through A2BR activation in the face of agonistic anti-CD137 treatment. Our study demonstrates that CD73 blockade has critical implications for effective clinical targeting of CD137 and possibly other costimulatory molecules. Note: This abstract was not presented at the conference. Citation Format: Siqi Chen, Jie Fan, Donye Dominguez, Qin Lei, Alan Long, Deyu Fang, Bin Zhang. CD73 BLOCKADE OVERCOMES RESISTANCE TO AGONISTIC ANTI-CD137 ANTIBODY THERAPY IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-117.
Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries
Authors: Guy Young, Miguel A. Escobar, Steven W. Pipe, David L. Cooper
Journal: American Journal of Hematology (2017)

Self-administration of factor and bypassing agents by persons with hemophilia in the home setting is recommended to facilitate earlier intervention after bleeding episodes. The objective of this review was to summarize recombinant activated coagulation factor VII (rFVIIa) safety and efficacy data from clinical trials and patient registries documenting use in the home treatment setting in people with congenital hemophilia with inhibitors (CHwI). A total of 16 studies and registries were identified for inclusion; 14 evaluated on-demand treatment of acute bleeding episodes (865 patients, 9024 bleeding episodes) and 2 evaluated use for secondary prophylaxis (108 patients, 42,861 prophylaxis days). In the on-demand studies, efficacy was consistently high (81%-96%), and thrombotic events were uncommon (n = 3). In the secondary prophylaxis studies, rFVIIa was associated with a 45% to 59% reduction in bleeding episodes and no thrombotic events. These data support the clinical practice of administering rFVIIa in patients in the home treatment setting after initiation under a physician's care.
Optimal timing for hepatitis C antiviral therapy in the peritransplant period?
Authors: George Cholankeril, Robert J. Wong, Donghee Kim, Aijaz Ahmed
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Wong advises, is on the speakers' bureau, and received grants from Gilead. To the Editor: In their recent study, Chhatwal et al. performed a Markov‐based microsimulation comparing pretransplant versus posttransplant treatment with direct‐acting antiviral (DAA) agents in hepatitis C virus (HCV)–infected patients with decompensated cirrhosis who are awaiting liver transplantation (LT).1 The study concluded that the optimal Model for End‐Stage Liver Disease (MELD) score threshold for pretransplant treatment ranges between 23 and 27, depending on median wait time to LT within a United Network for Organ Sharing (UNOS) region. We think these recommendations should be reevaluated. Our concerns are as follows. The UNOS regional MELD score thresholds for pretransplant DAA therapy should be further subdivided into ABO blood groups. For instance, the MELD score thresholds of 23 and 27 in UNOS regions 3 and 9, respectively, also approximate the mean MELD score at LT within these regions for blood type AB.2 This threshold may result in "MELD purgatory" among patients with this rare blood type. Less profound variations in other ABO blood groups may exist as well and should be adjusted for in this model. In 2016, UNOS region 5 experienced the highest regional mean MELD score of 32 at LT, which is not reflected in wait time to LT.2 Without adjusting for regional variation in mean MELD score at LT and the mortality associated with it, this model may underestimate the threshold for pretransplant treatment in UNOS regions with organ shortage and high mean MELD at LT. Because this was not a cost‐effectiveness analysis, HCV‐positive donor grafts should not have been excluded from this analysis given the excellent response rates with DAA agents in the posttransplant setting. In addition, the national percentage of usable HCV‐positive donor grafts is reported to be under 5%, considerably lower than the 8% estimate used in this analysis.3 The following clinical outcomes were not assessed and should also be considered in the timing of DAA therapy: delisting due to clinical improvement or deterioration, reduction in posttransplant fibrosing cholestatic recurrent HCV infection, and reduction in retransplantation rates. The impact of Regional Share 35 and sodium‐MELD policies as well as regional variation in MELD exception should have been included in the sensitivity analyses.4 Finally, an individualized treatment algorithm was proposed in the editorial. But the importance of patient preference should have been stressed.
Association of family history and location of BRCA1 and BRCA2 mutations in triple-negative breast cancer patients.
Authors: Yen Yen Tan, Daniela Muhr, Christine Rappaport-Fuerhauser, Daphne Gschwantler-Kaulich, Christoph Grimm, Stephan Polterauer, Georg Pfeiler, Andreas Berger, Muy-Kheng Maria Tea, Christian F. Singer
Journal: Journal of Clinical Oncology (2017)

e12588 Background: We assessed the prevalence of family history and its association with germline BRCA1/2mutation status/location and age at onset in triple-negative breast cancer (TNBC) patients. Methods: 266 patients with TNBC &lt; 60 years unselected for family history of cancer were enrolled and germline DNA was sequenced to identify mutations. Family pedigrees were prospectively collected from these patients. Logistic regression was used to investigate family history and its association with mutation type/location and age at onset. ROC curves were constructed to determine good predictors of BRCAmutations. Results: BRCA mutations were identified in 18.0% of all patients (15.0% BRCA1, 3.0% BRCA2). BRCA1 carriers have a significantly earlier age at onset than non-mutation carriers (40 vs 49 years; p &lt; .001). While 39/124 (31.4%) patients with family history of cancer carried a BRCA1/2 mutation, 9/142 (6.3%) BRCA carriers had no family history of cancer. BRCA1 carriers with ≥1BC in the family are commonly identified in the breast cancer cluster regions (53.1%). BRCA2 carriers more commonly cluster within the ovarian cancer regions. Of note, this difference was not statistically significant. Women with mutations in BRCA1 OCCR are diagnosed at a younger age. TNBC diagnosed ≤45 years with ≥1BC and ≥1OC in the family are good predictors of BRCA1 mutation (AUC 0.867). Conclusions: Young women with TNBC and a family history of BC and OC are likely to have a BRCA mutation. Specific BRCA mutation locations may add to the identification of a subgroup of TNBC patients with a relatively higher risk of subsequent ovarian cancer. Identification of high-risk TNBC patients with BRCA1 mutation will enable clinicians to optimize cancer management for this phenotype, but will require further validation in larger studies.
Erratum: Corrigendum: Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability
Authors: Christopher A Jones, Nyall R London, Haoyu Chen, Kye Won Park, Dominique Sauvaget, Rebecca A Stockton, Joshua D Wythe, Wonhee Suh, Frederic Larrieu-Lahargue, Yoh-suke Mukouyama, Per Lindblom, Pankaj Seth, Antonio Frias, Naoyuki Nishiya, Mark H Ginsberg, Holger Gerhardt, Kang Zhang, Dean Y Li
Journal: Nature Medicine (2008)
THE FEASIBILITY OF A SPORTS PHYSICAL THERAPIST LED IMPLEMENTATION OF A PREVENTIVE TRAINING PROGRAM IN A DUTCH AMATEUR FOOTBALL CLUB
Authors: Maartje Verheul, Maarten Barendrecht
Journal: British Journal of Sports Medicine (2017)

Background Preventive training programs are effective in reducing injury risk but the implementation of these programs on club level remains a challenge. The sports physical therapist (SPT) could play an important role in this process. The feasibility of a SPT led implementation process has not yet been investigated. Objective To investigate the feasibility of a SPT led implementation of a preventive warm-up program in a Dutch amateur football club. Design Implementation study. Setting A Dutch amateur football club. Patients (or Participants) Club officials, trainers, coaches and athletes. Interventions (or Assessment of Risk Factors) SPT led implementation of the FIFA11+ warm-up program on all club levels in a Dutch amateur football club. Main Outcome Measurements Tasks and time-management of the SPT. Effectiveness of different aspects of the implementation process using the RE-AIM framework. Results Important tasks on sports medical subjects were the development of a training program adjusted to the context and the adopters, and yearly coach education (workshops and manuals). Management tasks consisted of the composition of an implementation team and plan, and the support of this team during the implementation process. Overall during the first season it took the SPT 50 hours to complete these tasks. After one season adoption (88.4%) and implementation (88.9%) on trainer level as well as maintenance on club level (&gt;92%) were high. Conclusions A SPT led implementation process of an injury prevention program in an amateur football club seems a feasible option to change club level policy and behaviour on injury prevention, in addition to implementation strategies on national level and in coach education. Prospective randomized trials are needed to investigate the additional effectiveness of such club level implementation.
Evaluation of simplified lymphatic microsurgical preventing healing approach (SLYMPHA) for the prevention of breast cancer-related clinical lymphedema after axillary lymph node dissection.
Authors: Tolga Ozmen, Mesa Lazaro, Yan Zhou, Alicia Vinyard, Eli Avisar
Journal: Journal of Clinical Oncology (2017)

563 Background: Lymphedema (LE) is a serious complication of axillary lymph node dissection (ALND) with an incidence rate of 16%. Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) has been proposed as an effective adjunct to ALND for the prevention of LE. This procedure however requires microsurgical techniques. The aim of this study was to assess the efficiency of Simplified-LYMPHA (SLYMPHA) in preventing LE in a prospective cohort of patients. Methods: All patients, undergoing ALND with or without SLYMPHA between January 2014 and December 2016 were included in the study. SLYMPHA is a slightly modified and simplified version of LYMPHA. It is performed by the operating surgeon performing the ALND. One or more lymphatic channels identified by reverse arm mapping are inserted using a sleeve technique into the cut end of a neighboring vein. During follow-up visits, tape-measuring limb circumference method was used to detect clinical LE. Demographic, clinical, surgical and pathologic factors were recorded. The incidence of clinical LE was compared between ALND with and without SLYMPHA. Univariate and multivariate analysis were used to assess the role of other factors in the appearance of clinical LE. Results: 406 patients were included in the study. SLYMPHA procedure was attempted in 81 patients and was completed successfully in 90% of patients. Early complication rates were similar between patients who underwent SLYMPHA and who did not (4% vs. 4.13%; p = 0.948). Median follow-up time was 15±13.73 [1-32] months. Patients, who underwent SLYMPHA, had a significantly lower rate of clinical LE both in univariate and multivariate analysis (3% vs 19%; p = 0.001; OR 0.12 [0.03-0.5]). Excising &gt; 22 lymph nodes and a co-diagnosis of diabetes were also correlated with higher clinical LE rates on univariate analysis, but only excising &gt; 22 lymph nodes remained to be significant on multivariate analysis. Conclusions: SLYMPHA is a safe and relatively simple method, which decreases incidence of clinical LE dramatically. It should be considered as an adjunct procedure to ALND for all patients during initial surgery.