tbuckley/cabot-search huggingface dataset:
NCCN Guidelines as a Model of Extended Criteria for Lung Cancer Screening
Authors: Brady J. McKee, Shawn Regis, Andrea K. Borondy-Kitts, Jeffrey A. Hashim, Robert J. French, Christoph Wald, Andrea B. McKee
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: This review assessed the performance of patients in NCCN high-risk group 2 in a clinical CT lung screening (CTLS) program. Methods: We retrospectively reviewed screening results for all patients from our institution undergoing clinical CTLS from January 2012 through December 2016, with follow-up through June 2017. To qualify for screening, patients had to meet the NCCN Guidelines high-risk criteria for CTLS, have a physician order for screening, be asymptomatic, be lung cancer–free for 5 years, and have no known metastatic disease. We compared demographics and screening performance of NCCN high-risk groups 1 and 2 across >4 rounds of screening. Screening metrics assessed included rates of positive and suspicious examinations, significant incidental and infectious/inflammatory findings, false negatives, and cancer detection. We also compared cancer stage and histology detected in each NCCN high-risk group. Results: A total of 2,927 individuals underwent baseline screening, of which 698 (24%) were in NCCN group 2. On average, group 2 patients were younger (60.6 vs 63.1 years), smoked less (38.8 vs 50.8 pack-years), had quit longer (18.1 vs 6.3 years), and were more often former smokers (61.4% vs 44.2%). Positive and suspicious examination rates, false negatives, and rates of infectious/inflammatory findings were equivalent in groups 1 and 2 across all rounds of screening. An increased rate of cancer detection was observed in group 2 during the second annual (T2) screening round (2.7% vs 0.5%; P=.005), with no difference in the other screening rounds: baseline (T0; 2% vs 2.3%; P=.61), first annual (T1; 1.2% vs 1.7%; P=.41), and third annual and beyond (≥T3; 1.2% vs 1.1%; P=1.00). Conclusions: CTLS appears to be equally effective in both NCCN high-risk groups.
Genomic landscapes of brain metastasis patients of colorectal cancer to reveal clinical potential of individualized therapies.
Authors: Jing Sun, Cheng Wang, Yayun Gu, Jian Yu, Zhibin Hu, Yanhong Gu
Journal: Journal of Clinical Oncology (2018)

674 Background: Brain metastasis (BM) from colorectal cancer (CRC) is rare with 0.6-2.9% incidence rising in decades partly due to improved systemic treatment and prolonged survival. CRC patients had poor prognosis after BM because of lack of effective therapy. Commonly, only isolated BM of CRC patients are candidates for surgery and decisions for individualized therapies in patients with BM are often made according to primary-tumor biopsies, however, whether genomic features were similar in BMs and in primary CRC remained unknown. Thus, it is urgent to describe the molecular landscapes of BM genomics and to identify potentially clinically informative alterations. Methods: We conducted whole-exome sequencing on 15 “trios” of patient-matched brain metastases, primary CRC tumors, and adjacent-normal samples. Sequencing data processing and analysis were performed using pipeline of GATK best practice. Mutect2 algorithm were used to identify somatic substitutions in targeted exons. Clonal Evolution Suite was applied to evaluatecancer-cell fraction (CCF) for each mutation. Results: We identified 24,988 somatic mutations from CRC and their paired BM. In addition to the signature of age, we deciphered two mutational signatures, which was indicators of homologous recombination deficiency (HRD) and DNA mismatch repair deficiency (MMRD) respectively. The fraction of two signatures were significantly higher in BM than in primary CRC samples ( P&lt; 0.001). Further analysis revealed BM-specific mutations (CCF BM = 1 and CCF Primary &lt; 0.5) in BRCA1 and BRCA2 and a significantly higher microsatellite instability status in BM patients ( P&lt; 0.05). Additional BM-specific mutations were identified in genes from TARGET database for which somatic alterations have therapeutic or prognostic implications. We identified recurrent BM-specific mutations in voltage-gated sodium channel proteins ( SNC7A and SCN2A). Conclusions: It has been proved that patients with advanced HRD and MMRD are sensitive to PARP inhibitors and PD-1 blockade respectively. We provide new candidate targets for molecular therapies. Our findings provide new clinical potential for individualized therapies of BM patients of CRC.
High Levels of <scp>DEK</scp> Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti–Tumor Necrosis Factor Therapy
Authors: Nirit Mor‐Vaknin, Miguel Rivas, Maureen Legendre, Smriti Mohan, Ye Yuanfan, Theresa Mau, Anne Johnson, Bin Huang, Lili Zhao, Yukiko Kimura, Steven J. Spalding, Paula W. Morris, Beth S. Gottlieb, Karen Onel, Judyann C. Olson, Barbara S. Edelheit, Michael Shishov, Lawrence K. Jung, Elaine A. Cassidy, Sampath Prahalad, Murray H. Passo, Timothy Beukelman, Jay Mehta, Edward H. Giannini, Barbara S. Adams, Daniel J. Lovell, David M. Markovitz
Journal: Arthritis & Rheumatology (2017)

Objective The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis ( JIA ), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA . We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA . Methods DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti–tumor necrosis factor (anti‐ TNF ) therapy. Recombinant His‐tagged full‐length DEK protein (1–375 amino acids [aa]) and the 187–375‐aa and 1–350‐aa His‐tagged DEK fragments made in a baculovirus system were used for enzyme‐linked immunosorbent assay ( ELISA ) and immunoblotting. The C‐terminal 25‐aa fragment of DEK was expressed in a glutathione S‐transferase–tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule. Results DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA , and were higher in patients with polyarticular JIA who had more active disease after cessation of anti‐ TNF therapy. Immunoblotting against the C‐terminal 25‐aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain. Conclusion DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA , and higher in patients who have disease flares after cessation of anti‐ TNF therapy. The C‐terminal 25‐aa fragment is the most immunogenic portion of DEK . These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management.
Small Intestine Microbiota Regulate Host Digestive and Absorptive Adaptive Responses to Dietary Lipids
Authors: Kristina Martinez-Guryn, Nathaniel Hubert, Katya Frazier, Saskia Urlass, Mark W. Musch, Patricia Ojeda, Joseph F. Pierre, Jun Miyoshi, Timothy J. Sontag, Candace M. Cham, Catherine A. Reardon, Vanessa Leone, Eugene B. Chang
Journal: Cell Host & Microbe (2018)
134PD Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)
Authors: M. Reck, M.A. Socinski, F. Cappuzzo, F. Orlandi, D. Stroyakovskiy, N. Nogami, D. Rodríguez-Abreu, D. Moro-Sibilot, C.A. Thomas, F. Barlesi
Journal: Journal of Thoracic Oncology (2018)
Drug misuse at heart of strategy to reduce violent crime
Authors: Eliza Slawther
Journal: BMJ (2018)

A “multiple strand approach involving a range of partners across different sectors” is needed to tackle violent crime in England and Wales, says the first strategy aimed at reducing serious violence.1

Amber Rudd, the home secretary, said that the government’s response “to violent crime must address the misuse of drugs” as a priority.

Speaking about the main drivers behind violent crime, she explained: “There is a strong link between drugs and violent crime.”

In a speech on 9 April to launch the strategy in London, she said: “We will focus on reducing the number of people who take drugs and we will also increase the number …
NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD
Authors: Rozemarijn Snoek, Jessica van Setten, Brendan J. Keating, Ajay K. Israni, Pamala A. Jacobson, William S. Oetting, Arthur J. Matas, Roslyn B. Mannon, Zhongyang Zhang, Weijia Zhang, Ke Hao, Barbara Murphy, Roman Reindl-Schwaighofer, Andreas Heinzl, Rainer Oberbauer, Ondrej Viklicky, Peter J. Conlon, Caragh P. Stapleton, Stephan J.L. Bakker, Harold Snieder, Edith D.J. Peters, Bert van der Zwaag, Nine V.A.M. Knoers, Martin H. de Borst, Albertien M. van Eerde
Journal: Journal of the American Society of Nephrology (2018)

Background Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD.Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at ≥18 years old.Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age ≥30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%).Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.
Sex Differences in Outcomes After STEMI
Authors: Edina Cenko, Jinsung Yoon, Sasko Kedev, Goran Stankovic, Zorana Vasiljevic, Gordana Krljanac, Oliver Kalpak, Beatrice Ricci, Davor Milicic, Olivia Manfrini, Mihaela van der Schaar, Lina Badimon, Raffaele Bugiardini
Journal: JAMA Internal Medicine (2018)

Previous works have shown that women hospitalized with ST-segment elevation myocardial infarction (STEMI) have higher short-term mortality rates than men. However, it is unclear if these differences persist among patients undergoing contemporary primary percutaneous coronary intervention (PCI).To investigate whether the risk of 30-day mortality after STEMI is higher in women than men and, if so, to assess the role of age, medications, and primary PCI in this excess of risk.From January 2010 to January 2016, a total of 8834 patients were hospitalized and received medical treatment for STEMI in 41 hospitals referring data to the International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC) registry (NCT01218776).Demographics, baseline characteristics, clinical profile, and pharmacological treatment within 24 hours and primary PCI.Adjusted 30-day mortality rates estimated using inverse probability of treatment weighted (IPTW) logistic regression models.There were 2657 women with a mean (SD) age of 66.1 (11.6) years and 6177 men with a mean (SD) age of 59.9 (11.7) years included in the study. Thirty-day mortality was significantly higher for women than for men (11.6% vs 6.0%, P < .001). The gap in sex-specific mortality narrowed if restricting the analysis to men and women undergoing primary PCI (7.1% vs 3.3%, P < .001). After multivariable adjustment for comorbidities and treatment covariates, women under 60 had higher early mortality risk than men of the same age category (OR, 1.88; 95% CI, 1.04-3.26; P = .02). The risk in the subgroups aged 60 to 74 years and over 75 years was not significantly different between sexes (OR, 1.28; 95% CI, 0.88-1.88; P = .19 and OR, 1.17; 95% CI, 0.80-1.73; P = .40; respectively). After IPTW adjustment for baseline clinical covariates, the relationship among sex, age category, and 30-day mortality was similar (OR, 1.56 [95% CI, 1.05-2.3]; OR, 1.49 [95% CI, 1.15-1.92]; and OR, 1.21 [95% CI, 0.93-1.57]; respectively).Younger age was associated with higher 30-day mortality rates in women with STEMI even after adjustment for medications, primary PCI, and other coexisting comorbidities. This difference declines after age 60 and is no longer observed in oldest women.
Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study
Authors: Sarah F Keller, Na Lu, Kimberly G Blumenthal, Sharan K Rai, Chio Yokose, Jee Woong J Choi, Seoyoung C Kim, Yuqing Zhang, Hyon K Choi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objectives</h3> To examine associations of race/ethnicity and purported risk factors with hospitalised allopurinol-associated severe cutaneous adverse reactions (AASCARs). <h3>Methods</h3> We used US Medicaid data to identify incident allopurinol users between 1999 and 2012. We examined the risk of hospitalised AASCARs according to race/ethnicity and purported key risk factors and calculated relative risks (RR). <h3>Results</h3> Among 400 401 allopurinol initiators, we documented 203 hospitalised AASCAR cases (1 in 1972 initiators). The average AASCAR hospitalisation was 9.6 days and 43 individuals (21%) died. The multivariable-adjusted RRs for AASCARs among blacks, Asians and Native Hawaiians/Pacific Islanders compared with whites or Hispanics were 3.00 (95% CI 2.18 to 4.14), 3.03 (95% CI 1.72 to 5.34) and 6.68 (95% CI 4.37 to 10.22), respectively. Female sex, older age (≥60 years), chronic kidney disease and initial allopurinol dose (&gt;100 mg/day) were independently associated with a 2.5-fold, 1.7-fold, 2.3-fold and 1.9-fold higher risk of AASCAR, respectively. In our combined demographic analysis, older women (≥60 years) of a high-risk race/ethnicity (blacks, Asians or Native Hawaiians/Pacific Islanders) had over a 12-fold higher risk of hospitalised AASCARs than younger men of a low-risk race/ethnicity (whites or Hispanics) (multivariable-adjusted RR, 12.25; 95% CI 6.46 to 23.25). <h3>Conclusions</h3> This racially diverse (yet mostly white) cohort study indicates that the risk of hospitalised AASCAR is rare overall, although blacks, Asians and Native Hawaiians/Pacific-Islanders have a substantially higher risk of hospitalised AASCARs, particularly among older women. These data also support the practice of initiating allopurinol at a low dose (eg, ≤100 mg/day).
Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.
Authors: Premal H. Thaker, William Hampton Bradley, Charles A. Leath, Camille Catherine Gunderson, Nicholas Borys, Khursheed Anwer, Lauren Musso, Ronald David Alvarez
Journal: Journal of Clinical Oncology (2017)

155 Background: This study evaluated weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective of this study was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives were objective clinical response and pathological complete response at interval debulking surgery (IDB). Methods: This protocol followed a standard 3+3 design. Patients received GEN-1 at escalating dose levels from 36 mg/m 2 , 47 mg/m 2 , 61 mg/m 2 , to 79 mg/m 2 weekly for 8 treatments with concurrent T/C. After IDB, patients did not receive further GEN-1 but continued on T/C. Patients were assessed for dose limiting toxicities (DLT) and had tumor samples at a time of diagnostic laparoscopy and IDB. Translational endpoints are yet to be analyzed. Patients are being followed for every 3 months for 2 years. Results: Fifteen patients were enrolled and 9 patients received all 8 treatments with no DLTs. The 79 mg/m 2 GEN-1 cohort of patients are actively being treated. Two patients were screen failures; 1 patient discontinued prior to GEN-1 administration due to port site infection. Most common related toxicities were Gr 1 nausea, fatigue, abdominal pain, and vomiting. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. One patient did not undergo IDB due to pulmonary embolism and severe deconditioning due to underlying cancer. Of the other 8 patients undergoing IDB: 3/8 had stable disease, 4/8 had partial responses (PR), and 1/8 had complete response (CR). There was 1 pathological CR, 3 micro PR, and 3 macro PR. All patients had a ≥ 89% drop in CA-125 following GEN-1. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in NAC patients with newly diagnosed EOC. Updated results to be presented at meeting. Clinical trial information: NCT02480374.
Prediction of pancreatic cancer surgical outcomes and prognosis based on an objective resectability scoring system.
Authors: Diego Augusto Santos Toesca, Brooke Jeffrey, Rie von Eyben, Peter D. Poullos, George A. Poultsides, George A. Fisher, Brendan C. Visser, Albert Koong, Daniel Tandel Chang
Journal: Journal of Clinical Oncology (2018)

446 Background: There is no consensus on the best radiographic criteria to define pancreatic cancer (PCA) resectability. We undertook this study to objectively assess the probability of tumor resection based on quantitative measures of tumor abutment from the main peripancreatic vessels. Methods: Measurements of the circumferential degree and length of solid tumor contact with the superior mesenteric artery, the celiac artery/common hepatic artery, and superior mesenteric vein/portal vein were obtained through curved planar reformations from diagnostic CT images of PCA patients treated at our institution between 2001 and 2015. Results: A total of 399 patients were identified, of which 294 were used for the analysis. Of them, 113 (38.4%) were resected, 71 (62.8%) with negative margins (R0). Based on the individual measurements of vascular involvement, a resectability scoring system (RSS) was created (table), and used in a classification and regression tree model that correlated strongly with resection (p &lt; 0.0001) and R0 resection (p &lt; 0.0001) probabilities. The RSS demonstrated a higher PPV, NPV and accuracy (94.3%; 98.6%; 97%) to predict resection compared to the NCCN (90.8%; 96.7%; 94.5%) and MDACC resectability criteria (87.1%; 97.9%; 93.5%). Moreover, the RSS correlated with overall survival (OS) (p &lt; 0.0001) and metastasis-free survival (p &lt; 0.0001). Conclusions: We developed a PCA resectability scoring system that is objective, reproducible, and highly correlated with surgical outcomes and prognosis. External validation is warranted. [Table: see text]
Development and Validation of a Novel Evidence‐Based Lupus Multivariable Outcome Score for Clinical Trials
Authors: Michal Abrahamowicz, John M. Esdaile, Rosalind Ramsey‐Goldman, Lee S. Simon, Vibeke Strand, Peter E. Lipsky
Journal: Arthritis & Rheumatology (2018)

Objective Trials of new systemic lupus erythematosus ( SLE ) treatments are hampered by the lack of effective outcome measures. To address this, we developed a novel Lupus Multivariable Outcome Score (Lu MOS ) and assessed its performance using data from 2 randomized controlled trials of belimumab in patients with SLE . Methods The Lu MOS formula was developed by analyzing raw data from 2 pivotal trials, the Study of Belimumab in Subjects with SLE 52‐week ( BLISS ‐52) and 76‐week ( BLISS ‐76) trials, which are the basis for approval of belimumab. Using the BLISS ‐76 trial data as the learning data set, we carried out multivariable logistic regression analyses to optimize discrimination of outcomes between patients treated with 10 mg/kg belimumab and patients receiving placebo over the first 52 weeks of follow‐up. In addition, the performance of Lu MOS was assessed using an independent validation data set from the BLISS ‐52 trial. Results The Lu MOS model incorporated the following response criteria: a ≥4‐point reduction on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, an increase in C4 levels, a decrease in anti–double‐stranded DNA titers, and changes in the British Isles Lupus Assessment Group scores for organ system manifestations (no worsening in renal components, and improvements in mucocutaneous components). A decrease in the prednisone dose and increase in C3 levels had very minor impacts on the total Lu MOS score. In all analyses of the BLISS ‐76 and BLISS ‐52 trial data sets, the mean Lu MOS scores were significantly higher ( P &lt; 0.0001) in patients treated with 1 mg or 10 mg belimumab compared to placebo. In contrast to the performance of the SLE Responder Index 4 ( SRI ‐4), the Lu MOS revealed significant differences between the active treatment group (1 mg belimumab in the BLISS ‐76 cohort) and placebo group. The effect sizes were significantly much higher with the Lu MOS than with the SRI ‐4. Conclusion The evidenced‐based Lu MOS outcome scoring system, developed with data from the BLISS ‐76 trial of belimumab in patients with SLE and validated with data from the BLISS ‐52 trial, exhibits a superior capacity to discriminate responders from nonresponders when compared to the SRI ‐4. Use of the Lu MOS may improve the efficiency and power of analyses in future lupus trials.
Risk factors for upgrading and upstaging of pre-operative biopsies in ductal carcinoma in situ
Authors: G S Mannu, E Groen, Z Wang, M Schaapveld, E Lips, M Chung, I Joore, F van Leeuwen, J Teerstra, Winter-Warnars Gao., S C Darby, J Wesseling
Journal: Cancer Research (2018)
Mechanisms of Cardiac Repair and Regeneration
Authors: Kathleen M. Broughton, Bingyan J. Wang, Fareheh Firouzi, Farid Khalafalla, Stefanie Dimmeler, Francisco Fernandez-Aviles, Mark A. Sussman
Journal: Circulation Research (2018)

Cardiovascular regenerative therapies are pursued on both basic and translational levels. Although efficacy and value of cell therapy for myocardial regeneration can be debated, there is a consensus that profound deficits in mechanistic understanding limit advances, optimization, and implementation. In collaboration with the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes), this review overviews several pivotal aspects of biological processes impinging on cardiac maintenance, repair, and regeneration. The goal of summarizing current mechanistic understanding is to prompt innovative directions for fundamental studies delineating cellular reparative and regenerative processes. Empowering myocardial regenerative interventions, whether dependent on endogenous processes or exogenously delivered repair agents, ultimately depends on mastering mechanisms and novel strategies that take advantage of rather than being limited by inherent myocardial biology.