tbuckley/cabot-search huggingface dataset:
Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents
Authors: Alawi H. Habara, Elmutaz M. Shaikho, Martin H. Steinberg
Journal: American Journal of Hematology (2017)

Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.
Regulatory data are hidden in plain sight
Authors: Harriet G Rosenberg, Adrienne Shnier
Journal: BMJ (2017)

The editorial by Doshi and Godlee rightly argues for better communication among regulatory scientists, medical journals, and the public, especially when evidence held by regulators differs from journal publications.1 Watchdog groups, such as the health reform group of Public Citizen, routinely access material posted online by the US Food and Drug Administration, but …
Abstract 14981: The Gut Hormone Ghrelin Partially Reverses Energy Substrate Metabolic Alterations in the Failing Heart
Authors: Gianfranco Mitacchione, Jeffery Powers, Gino Grifoni, Marykathryn Hurst, Anna M Kulczycki, Amy Lam, Lien Ly, Fabio Settanni, Riccarda Granata, Fabio Recchia
Journal: Circulation (2013)

The gut-derived hormone ghrelin, particularly in acylated form, plays a major role in daily regulation of systemic metabolism. Studies show that acyl ghrelin also exerts cardioprotective effects, hence its testing for treatment of human heart failure. Whether ghrelin can directly modulate cardiac energy substrate metabolism is presently unknown. We tested this hypothesis in chronically instrumented, conscious dogs: 5 with pacing-induced congestive heart failure (HF) and 4 normal controls. 1.2 nmol/kg/hour of human des-acyl ghrelin was infused intravenously for 15 min followed by 60 min washout (a return to baseline plasma ghrelin concentrations was confirmed post-washout) and then a subsequent infusion of acyl ghrelin at the same dose. 3H-oleate and 14C-glucose were co-infused, and paired blood samples were withdrawn from aorta and coronary sinus to measure cardiac oxygen consumption, free fatty acid (FFA) and glucose oxidation, and lactate uptake. Consistent with previous findings, baseline FFA and glucose oxidation were, respectively, 60% lower and threefold higher in HF compared to normal. Neither des-acyl ghrelin nor acyl ghrelin affected significantly cardiac function or hemodynamics. However, in HF we found the following changes in response to des-acyl ghrelin and acyl ghrelin, respectively: FFA oxidation increased from 11.68±1.0 to 15.4±1.3 and from 15.4±1.8 (post-washout) to 17.8±1.9nmol/beat (all P
Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study
Authors: Philip E. Silkoff, Susan Flavin, Robert Gordon, Mathew J. Loza, Peter J. Sterk, Rene Lutter, Zuzana Diamant, Ronald B. Turner, Brian J. Lipworth, David Proud, Dave Singh, Andreas Eich, Vibeke Backer, James E. Gern, Christian Herzmann, Scott A. Halperin, Tjeert T. Mensinga, Alfred M. Del Vecchio, Patrick Branigan, Lani San Mateo, Frédéric Baribaud, Elliot S. Barnathan, Sebastian L. Johnston
Journal: Journal of Allergy and Clinical Immunology (2017)
Association of MLL2 mutation positive non-small cell lung cancer with prognosis.
Authors: Fatemeh Ardeshir-Larijani, Gary Wildey, Pingfu Fu, Priyanka Bhateja, Mary Beth Lipka, Afshin Dowlati
Journal: Journal of Clinical Oncology (2017)

11598 Background: Myeloid/lymphoid or mixed-lineage leukemia protein 2 (MLL2) is an epigenetic regulator expressed in many tissues. Although MLL2 mutations are associated with poor prognosis in different types of cancer, the clinical impact of this gene in lung cancer remains unclear. Here, we evaluated the clinical and genomic characteristics of MLL2 alteration in non-small cell lung cancer (NSCLC) and compared it to small cell lung cancer (SCLC) Methods: Between 2014 and 2016 tumor samples of 194 Stage III and IV NSCLC patients and 50 SCLC patients underwent targeted-exome sequencing. The association of MLL2 mutation with survival outcomes was measured using KaplanMeier methods (PFS, OS). Coxs proportional hazards regression model was performed for multivariate survival analyses with known clinical prognostic features. All tests were two-sided and p-values = 0.05 were considered statistically significant. Results: The MLL2 mutation rate was 17.5% (N=34) in NSCLC. Patients with mutant MLL2 had significantly lower overall survival (OS) (9.97 vs. 30.2 months, p &lt; 0.0001) and progression-free survival (PFS) (8.46 vs. 24.1 month, p = 0.0007) compared to those with wild type MLL2. The median overall survival in the entire NSCLC cohort was 23.3 months (95% CI: 16.5  34.4). Interestingly, MLL2 mutation was significantly more common in females (p = 0.017). There was no significant association of MLL2 mutation status with age, smoking history, race or histology . Using a multivariate Cox regression model with adjustments based on tumor stage, smoking histology and chemotherapy, MLL2 mutation remained the most remarkable prognostic factor in NSCLC: OS Hazard Ratio 2.79, p = 0.0001 and PFS Hazard Ratio 1.99, p &lt; 0.001. By comparison, the MLL2 mutation rate in SCLC was 24% (N=12) and showed no gender bias (p=0.874). There was no significant decrease in survival associated with MLL2 mutation in SCLC (OS p = 0.966, PFS p = 0.641). Conclusions: This study demonstrates that MLL2 mutation specifically impacts survival outcome only in NSCLC but not SCLC.
Screening Pelvic Examinations
Authors: Amir Qaseem, Linda Humphrey, Mary Ann Forciea
Journal: JAMA (2017)

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Benefits and Harms of Treatment of Asymptomatic Bacteriuria: A Systematic Review and Meta-analysis by the European Association of Urology Urological Infection Guidelines Panel
Authors: Bela Köves, Tommaso Cai, Rajan Veeratterapillay, Robert Pickard, Thomas Seisen, Thomas B. Lam, Cathy Yuhong Yuan, Franck Bruyere, Florian Wagenlehner, Riccardo Bartoletti, Suzanne E. Geerlings, Adrian Pilatz, Benjamin Pradere, Fabian Hofmann, Gernot Bonkat, Björn Wullt
Journal: European Urology (2017)
Mast Cells Granular Contents Are Crucial for Deep Vein Thrombosis in Mice
Authors: Tatyana Ponomaryov, Holly Payne, Larissa Fabritz, Denisa D. Wagner, Alexander Brill
Journal: Circulation Research (2017)

Deep vein thrombosis (DVT) and its complication pulmonary embolism have high morbidity reducing quality of life and leading to death. Cellular mechanisms of DVT initiation remain poorly understood.We sought to determine the role of mast cells (MCs) in DVT initiation and validate MCs as a potential target for DVT prevention.In a mouse model, DVT was induced by partial ligation (stenosis) of the inferior vena cava. We demonstrated that 2 strains of mice deficient for MCs were completely protected from DVT. Adoptive transfer of in vitro differentiated MCs restored thrombosis. MCs were present in the venous wall, and the number of granule-containing MCs decreased with thrombosis. Pharmacological depletion of MCs granules or prevention of MC degranulation also reduced DVT. Basal plasma levels of von Willebrand factor and recruitment of platelets to the inferior vena cava wall after DVT induction were reduced in MC-deficient mice. Stenosis application increased plasma levels of soluble P-selectin in wild-type but not in MC-deficient mice. MC releasate elevated ICAM-1 (intercellular adhesion molecule-1) expression on HUVEC (human umbilical vein endothelial cells) in vitro. Topical application of compound 48/80, an MC secretagogue, or histamine, a Weibel-Palade body secretagogue from MCs, potentiated DVT in wild-type mice, and histamine restored thrombosis in MC-deficient animals.MCs exacerbate DVT likely through endothelial activation and Weibel-Palade body release, which is, at least in part, mediated by histamine. Because MCs do not directly contribute to normal hemostasis, they can be considered potential targets for prevention of DVT in humans.
Optimizing Genotype Matched Clinical Trial (GMCT) accrual in a community oncology program (COP).
Authors: Steven Francis Powell, Elie G. Dib, Jonathan Scott Bleeker, Michael D. Keppen, Miroslaw Mazurczak, Keely Marie Hack, Mark Mutuota Gitau, Preston D. Steen, Shelby A. Terstriep, John Reynolds, Jayan Nair, Megan L Landsverk, Chun-Hung Chan, Paul A. Thompson, Christie Ellison, Lora Jane Black, James M. Ford, Anu G. Gaba
Journal: Journal of Clinical Oncology (2016)

e18036 Background: While molecular profiling (MP) is becoming widely accessible, clinician understanding may be a barrier to GMCT enrollment. MP programs at academic medical centers report GMCT enrollment rates at 5-17% of eligible patients. To advance precision medicine, this process must be adapted to serve COPs. Methods: We performed a prospective MP study (NCT02416518) at Sanford Health, a predominantly rural health care system with 4 participating COP sites. The primary outcome of the study was feasibility of testing in this setting. Secondary outcomes included correlating GMCT enrollment, impact on treatment decisions, and patient outcomes. Eligible patients included those with incurable solid tumor malignancies that had progressed on ≥ 1 prior line of therapy or had no standard first-line treatment options available, an ECOG PS of ≤ 1, adequate organ function, and recent tissue biopsy ( ≤ 14 weeks) available for MP. MP was performed using FoundationOne. A weekly, video conferenced genomic tumor board (GTB), composed of COP providers, reviewed each case for actionable alterations (AAs) and provided recommendations to the treating physician. Results: From June 2014-Dec 2015, 145 patients signed consent to participate in the prospective MP study. 120 patients were eligible for testing and 109 had reviewable MP results. Reasons for failure to complete MP included: insufficient tissue (n = 8), decline in clinical status (n = 2), and withdrawal of consent (n = 1). 99 (90.8%) of those with reviewable results had at least one AA that was felt to have a rational therapeutic option based on GTB review. Of those with an AA, 39 (39.4%) were treated based on their MP findings. 16 (16.2%) of those with an AA enrolled in GMCTs. 7 (7.1%) were treated with FDA approved on-label drug and 16 (16.2%) were treated with FDA approved off-label drug. Patient outcomes are being tracked in accordance with the corresponding GMCTs and for those treated with off-label drug. Conclusions: Development of a system-wide MP program in the community is feasible and can optimize accrual to GMCTs. This program will be adapted to enrich patient enrollment into rapidly emerging GMCTs available through the National Cancer Institute (NCI) and industry. Clinical trial information: NCT02416518.
Pembrolizumab in patients with advanced cervical squamous cell cancer: Preliminary results from the phase Ib KEYNOTE-028 study.
Authors: Jean-Sebastien Frenel, Christophe Le Tourneau, Bert H. O'Neil, Patrick Alexander Ott, Sarina Anne Piha-Paul, Carlos Alberto Gomez-Roca, Emilie Van Brummelen, Hope S. Rugo, Shari Thomas, Sanatan Saraf, Mei Chen, Andrea Varga
Journal: Journal of Clinical Oncology (2016)

5515 Background: Median survival is limited to only ~7 months in patients (pts) with metastatic or recurrent cervical cancer despite current treatments. Upregulation of the PD-1/PD-L1 pathway on tumor or infiltrating immune cells may negatively regulate immunity and contribute to disease progression. Pembrolizumab, an anti–PD-1 antibody, blocks the interaction between PD-1 and its ligands, PD-L1/PD-L2. Results from the cervical cancer cohort of KEYNOTE-028 (NCT02054806), a phase 1b study to evaluate the safety and efficacy of pembrolizumab in pts with advanced solid tumors, are presented. Methods: Key eligibility criteria included advanced cervical squamous cell cancer, failure of prior systemic therapy, ECOG PS 0-1, and PD-L1 expression in ≥1% of tumor or stroma cells by IHC. Pembrolizumab 10 mg/kg was given every 2 wk for up to 24 mo or until confirmed progression, intolerable toxicity, death, or withdrawal of consent. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. The primary end point was ORR per RECIST v1.1 by investigator assessment. Results: 24 pts with advanced cervical cancer were enrolled; median age was 41.5 y, 75.0% had an ECOG PS of 1, and 62.5% had received ≥2 prior therapies for metastatic disease. As of Dec 10, 2015, median follow-up duration was 48.9 wk (range, 5.6-90 wk). 18 (75.0%) pts experienced a treatment-related adverse event (TRAE), with pyrexia (n =4) and rash (n = 3) occurring in ≥10% of pts. 5 (20.8%) pts had grade 3 TRAEs, 2 of whom discontinued pembrolizumab (colitis, Guillain-Barre syndrome). No grade 4 or 5 TRAEs occurred. ORR (confirmed) was 12.5% (3/24; 95% CI, 2.7%-32.4%; all were PRs); the median duration of response was 19.3 wk (range, 17.7-52.0 wk). The stable disease (SD) rate was 12.5% (3/24; 95% CI, 2.7%-32.4%); the median duration of SD was 19.6 wk (range, 16.3-29.7+ wk). The 6-mo PFS rate was 13.0%; the 6-mo OS rate was 66.7%. Conclusions: Pembrolizumab was well tolerated and showed promising antitumor activity in pts with PD-L1+ advanced cervical squamous cell cancer. The clinical benefit of pembrolizumab in advanced cervical cancer will be further investigated in the phase 2 KEYNOTE-158 trial (NCT02628067). Clinical trial information: NCT02054806.
Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males
Authors: Simona Pace, Carlo Pergola, Friederike Dehm, Antonietta Rossi, Jana Gerstmeier, Fabiana Troisi, Helmut Pein, Anja M. Schaible, Christina Weinigel, Silke Rummler, Hinnak Northoff, Stefan Laufer, Thorsten J. Maier, Olof Rådmark, Bengt Samuelsson, Andreas Koeberle, Lidia Sautebin, Oliver Werz
Journal: Journal of Clinical Investigation (2017)

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5α-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.
Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors.
Authors: Toshihiko Doi, Hiroji Iwata, Junji Tsurutani, Shunji Takahashi, Haeseong Park, Charles H. Redfern, Kohei Shitara, Chikako Shimizu, Hiroya Taniguchi, Tsutomu Iwasa, Shinichiro Taira, Albert C. Lockhart, Jennifer M. Fisher, Takahiro Jikoh, Yoshihiko Fujisaki, Caleb C. Lee, Antoine Yver, Kenji Tamura
Journal: Journal of Clinical Oncology (2017)

108 Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]
Hepatic Injury Following Reduced-Intensity Unrelated Cord Blood Transplantation for Adult Patients with Hematological Diseases.
Authors: Eiji Kusumi, Masahiro Kami, Yoshinobu Kanda, Kunihiko Seki, Masayo Fujiwara, Rikako Koyama, Tsunehiko Komatsu, Yuko Kodama, Tomoko Matsumura, Koichiro Yuji, Shigesaburo Miyakoshi, Shuichi Taniguchi
Journal: Blood (2006)
Genetic variations within the vitamin C transporter genes to predict outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Martin D. Berger, Sebastian Stintzing, Dongyun Yang, Shu Cao, Yuji Miyamoto, Mitsukuni Suenaga, Shivani Soni, Roel Gopez, Elizabeth Melendez, Wu Zhang, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

11507 Background: Vitamin C is involved in many critical metabolic processes. Beside its major role as an antioxidant and free radical scavenger vitamin C exerts a regulatory influence on angiogenesis. Additionally, epidemiologic studies show an association between vitamin C levels and incidence of cancer.We therefore hypothesize that variations in genes encoding for vitamin C transporter proteins may predict outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFIRI and bevacizumab (bev). Methods: Theimpact of 3 functional SNPs within the SVCT1, SVCT2 and Glut1 genes on outcome was evaluated in 292 pts with mCRC treated with first-line FOLFIRI/bev in the randomized phase III FIRE-3 trial. 294 pts receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a negative control. Genomic DNA was extracted from formalin fixed paraffin embedded tissue and SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics in the FOLFIRI/bev arm were as follows: female/male 99/193; median age = 65y andmedian PFS/OS = 10.1/24.2 months (mts). The SVCT1 rs11242462 SNP showed significant association with PFS. T allele carriers had a longer median PFS compared to those with a C/C genotype (10.7 vs 9.7 mts) in both univariate (HR 0.77, p = 0.046) and multivariate analysis (HR 0.73, p = 0.028). The effect on outcome was most significant among KRAS mutant pts. Here, T allele carriers showed a markedly prolonged PFS and OS compared to pts with a C/C genotype (12.5 vs 7.0 mts, HR 0.50, p = 0.018 and 32.8 vs 14.7 mts, HR 0.45, p = 0.009). These associations remained significant in multivariate analyses (p = 0.009 and p = 0.021, respectively). However, the favorable impact on outcome was not observed among T allele carriers treated with FOLFIRI/cet. Conclusions: Our results provide the first evidence that the SVCT1 polymorphism rs11242462 might serve as a predictive marker in pts with mCRC treated with FOLFIRI/bev in the first-line setting. Targeting vitamin C transporter proteins might be a promising approach to further improve treatment options against mCRC and to overcome resistance to anti-angiogenic therapy.