tbuckley/cabot-search huggingface dataset:
Validation of <i>DPYD</i> variants <i>DPYD*2A, </i>I560S, and D949V as predictors of 5-fluorouracil (5-FU)-related toxicity in stage III colon cancer (CC) patients from adjuvant trial NCCTG N0147.
Authors: Adam Lee, Qian Shi, Emily S Pavey, Daniel J. Sargent, Steven R. Alberts, Frank A. Sinicrope, Jeffrey Berenberg, Richard M. Goldberg, Robert B. Diasio
Journal: Journal of Clinical Oncology (2013)

3510 Background: Prediction of 5-FU-related adverse events (5FU-AEs) continues to be problematic. Pharmacogenetic studies on the rate-limiting enzyme in 5-FU metabolism, dihydropyrimidine dehydrogenase (DPD), suggest a link between three variants and both decreased enzyme activity and increased toxicity: c.1905+1 G&gt;A (DPYD*2A; rs3918290), c.1679 T&gt;G (I560S; DPYD*13; rs55886062), and c.2846A&gt;T (D949V; rs67376798). Since the adverse impact of DPYD variants on 5-FU toxicity remains controversial, we determined associations between the three known DPYD variants and 5FU-AEs in stage III CC patients receiving FOLFOX or FOLFIRI (+ cetuximab) after curative resection. Methods: 2886 patients were genotyped by multiplexed single-base extension assays using the IPLEX Gold Kit and analyzed on the Sequenom MassARRAY system. Grade 3+ AEs were recorded per CTCAE v3. Fisher’s exact test, unequal variance two-sample t-test, and Wilcoxon rank sum test were used to compare categorical variables, continuous variables, and counts between patients with wild-type and mutant status. Logistic regressions were used to assess univariate and multivariate associations. Results: Patients displayed the following characteristics: male gender 53.2%, median age 58 [19-86], proficient DNA mismatch repair status 88.6%, PS-0 76.6%, + irinotecan 8.1%, and + cetuximab 45.9%. A total of 27 (0.9%), 4 (0.1%), and 32 (1.1%) patients carried the DPYD*2A, I560S, and D949V variants, respectively. Analysis identified significant associations between DPYD*2A and D949V variants and toxicity, with grade 3+ 5FU-AEs identified in 22 DPYD*2A carriers (OR=11.9, 95% CI 4.0-32.7, p&lt;0.0001) and 22 D949V carriers (OR=5.5, 95% CI 2.5-12.1, p&lt; 0.0001). No interaction effect was found between DPYD*2Aand D949V on grade 3+ 5FU-AEs (p = 0.98), nor on overall grade 3+ AEs (p = 0.97). No significant association was identified between I560S and grade 3+ 5FU-AEs. Conclusions: In the largest study to date, statistically significant associations were found between DPYD*2A and D949V variants and increased incidence of grade 3+ 5FU-AEs, suggesting utility in 5-FU toxicity prediction.
A phase I study of sirolimus in combination with metronomic therapy in children with recurrent and refractory solid/CNS tumors.
Authors: Muna Qayed, Thomas Cash, Mourad Tighiouart, Tobey MacDonald, Kelly C. Goldsmith, Leslie S. Kean, Patty Church, Howard M. Katzenstein
Journal: Journal of Clinical Oncology (2015)

10052 Background: Sirolimus, an oral mTOR inhibitor, has anti-tumor effects mainly by blocking signals which drive cells from G1 to S phase. It has antiangiogenic activity and has shown antitumor activity in pediatric solid tumor xenografts. At higher doses, with prolonged exposure, sirolimus has been shown to inhibit mTORC2 thereby inhibiting feedback loops that could lead to tumor growth. The safety of combining escalating doses of sirolimus with low dose metronomic chemotherapy was tested in a phase I trial. Methods: Patients ≤ 30 years of age with recurrent or refractory solid (including CNS ) tumors were eligible. Treatment consisted of continuous sirolimus and celecoxib (100 mg twice a day), oral etoposide (50 mg/m2/day, maximum dose 100mg) alternating every 21 days with oral cyclophosphamide (2.5 mg/kg/day, maximum dose 100mg) in 42 day cycles. The starting dose of sirolimus was 1 mg/m2 daily and was escalated by 0.5 mg/m2, following a Bayesian method of Escalation With Overdose Control. Samples for MTOR pathway evaluation in peripheral blood mononuclear cells were obtained during cycle 1. Results: 18 patients were enrolled: four on dose level (DL)1(one patient not evaluable), four on DL2, eight on DL3, and two on DL4. Median age was 11.0 years (2.3 – 19.4 years). Diagnoses included Ewing sarcoma, osteosarcoma, MPNST, rhabdoid tumor, retinoblastoma and CNS tumors (GBM, DIPG, high grade glioma, medulloblastoma, ependymoma, astrocytoma, PNET, GCT). One DLT (grade 4 neutropenia) was observed on DL2, two DLTs (grade 3 abdominal pain,grade 3mucositis) on DL3, and two DLTs (grade 3 dehydration, grade 3 mucositis) on DL4. The recommended phase II dose was determined to be 2 mg/m2 (DL3). Additional ≥ grade 3 regimen-related toxicities during cycle 1 were leukopenia, lymphopenia, thrombocytopenia, febrile neutropenia and vomiting. Best response was stable disease (SD) in 8 patients and partial response (PR) in one patient with GBM. One patient with high grade glioma was removed from study with SD due to toxicity and developed a PR without further therapy. Conclusions: The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is planned. Clinical trial information: NCT01331135.
Intensified local treatment and systemic therapy significantly increase time to progression and survival in patients with brain metastases from advanced breast cancer
Authors: R. Bartsch, S. Muschitz, C. Wenzel, K. Roessler, K. Dieckmann, H. Weitmann, U. Pluschnig, R. Poetter, C. C. Zielinski, G. G. Steger
Journal: Journal of Clinical Oncology (2006)

10536 Background: Brain metastases (BM) have evolved from a rare to a frequently encountered event in advanced breast cancer (ABC) due to advances in palliative systemic treatment. Especially since the introduction of trastuzumab, different groups reported an increased incidence of BM. In this study, we retrospectively tried to establish factors predicting a prolonged survival in those patients (P). Methods: All P treated at our centre from 1994 to 2004 with whole brain radiotherapy for BM from ABC were included. Cerebral time to progression (cTTP) and overall survival (OS) were calculated using the Kaplan-Meier product limit method. A multivariate analysis (Cox regression) was performed to explore which factors are able to influence significantly cTTP and OS (metastatic sites [visceral versus non-visceral], Karnofsky performance score [KPS], age, intensified local treatment [boost irradiation, neuro-surgical resection], further palliative systemic treatment). Results: Overall 174 P, median age 51 years (y), range 27–76 y, were included. Median cTTP was 3 months (m), range 1–33+ m (95% CI 4.67–7.37). Median OS was 7 m, range 1–44 m (95% CI 5.08– 8.92). Factors significantly influencing cTTP were KPS (p = 0.0024), intensified local treatment (p &lt; 0.0001), and palliative systemic treatment (P = 0.0003). Factors significantly influencing OS were intensified local treatment (p = 0.004), metastatic sites (p = 0.008), KPS (p = 0.006), and palliative systemic treatment (p &lt; 0.001). Conclusion: As shown by the significant influence of metastatic sites, some P die from their advanced systemic disease situation before they would experience cerebral progression, in part explaining the influence of systemic treatment. In other individuals however, intensified local treatment and systemic treatment appear to influence both cTTP and OS significantly, implicating a direct influence of systemic therapy on BM. This might result from an impaired blood brain barrier around metastatic sites, making sufficient tissue concentrations of cytotoxic agents possible. No significant financial relationships to disclose.
Final Analysis of a Multicenter Pilot Phase 2 Study of Ruxolitinib and Danazol in Patients with Myelofibrosis
Authors: Krisstina L. Gowin, Heidi E. Kosiorek, Amylou Constance Dueck, John Mascarenhas, Ronald Hoffman, Craig B. Reeder, John Camoriano, Veena Fauble, Raoul Tibes, Katherine Gano, Vineta Ghurye, Patricia Koenig, Ruben A. Mesa
Journal: Blood (2015)
Allogeneic Stem Cell Transplantation Improves Survival in Patients with FLT3-ITD-Negative and NPM1-Wild Type Intermediate Risk (ELN) Acute Myeloid Leukemia
Authors: Katharina Heidrich, Christian Thiede, Kerstin Schäfer-Eckart, Norbert Schmitz, Walter E Aulitzky, Alwin Krämer, Wolf Rösler, Mathias Hänel, Hermann Einsele, Claudia D. Baldus, Ralf U Trappe, Friedrich Stölzel, Jan Moritz Middeke, Christoph Röllig, Michael Kramer, Hubert Serve, Wolfgang E Berdel, Gerhard Ehninger, Martin Bornhäuser, Johannes Schetelig
Journal: Blood (2016)
Molecular Mechanism by Which Rituximab Sensitizes B-NHL Cells to TRAIL Apoptosis: Induction of RKIP and DR5 Expression Via Inhibition of NF-Kb, Snail, and YY1.
Authors: Mario I. Vega, Melisa Martinez-Paniagua, Sara Huerta-Yepez, Yeung Kam, Stavroula Baritaki, Benjamin Bonavida
Journal: Blood (2008)
Margo Mountjoy #HarpWhisperer #AthleteAdvocate #SheNeedsAClone
Authors: Johann Windt
Journal: British Journal of Sports Medicine (2017)

Establishing the Athlete Welfare programme at the Olympic Games. I worked on this for many years—to see it implemented in Rio in 2016 was a real career highlight for me. I hope this will protect athletes in the future, and prevent harassment and abuse in all sports!

…. Don’t ask!! ☺

Definitely the 2008 Olympic Games when I watched the inaugural 10k marathon swim in Beijing. I witnessed a disabled swimmer—Nathalie du Toit from South Africa—compete in the able-bodied event. Her courage and strength were inspiring.

While I could say some of the studies I have conducted, papers I have authored or the Olympic Games I have worked at, my most valuable contribution to the field is (hopefully) the help and care I give on a daily basis in my clinic to athletes of all shapes, sizes and abilities over the past 30 years.

The numerous athletes over the years that overcome adversity to strive for improvement and to reach personal goals—athletes who have overcome profound physical injury and emotional abuse issues. Their courage and fortitude make them all heroes in my eyes.

Perseverance, resilience and creativity. Wait—that is three skills; I guess another skill is not following exact directions!

Saying ‘yes’ when opportunities came my way. Although, in reality, I had to make some of my opportunities …
A phase I study of the gamma-secretase inhibitor RO4929097 and capecitabine in refractory solid tumors.
Authors: Noelle K. LoConte, Amye Tevaarwerk, Jill Kolesar, Kyle D. Holen, Sam Joseph Lubner, Daniel Mulkerin, William R. Schelman, Albiruni R.A. Razak, Lillian L. Siu, Jens C. Eickhoff, Lakeesha Carmichael, George Wilding, S. Percy Ivy, Glenn Liu
Journal: Journal of Clinical Oncology (2012)

3101 Background: RO4929097 is a oral inhibitor of gamma-secretase, which results in Notch signaling inhibition. Prior work has demonstrated that Notch-signaling inhibition enhances chemosensitivity of colon cancer cells. This study sought to combine RO4929097 with capecitabine (cape) and determine maximum tolerated dose (MTD), toxicities and efficacy. Preclinical and prior phase I work demonstrated possible autoinduction of RO4929097, so pharmacokinetic (PK) evaluation of RO4929097 and cape was planned. Methods: Adult patients with refractory solid tumors were eligible and received RO4929097 and cape at a fixed dose of 1000 mg/m2 BID with escalating doses of RO4929097 on a 21-day cycle according to a 3+3 design. Cape was administered for 14 days and the RO49029097 once daily, 3 days per week. RO4929097 plasma concentrations were evaluated by LC/MS/MS on days 3 and 10 of cycle 1, and PK parameters analyzed with WinNonLin version 5.2. Results: 4 dose levels have been completed (20, 30, 45 and 68 mg); 18 of 19 patients are evaluable for toxicity and PK data is available for 11 patients. One DLT has been observed (intolerable grade 2 fatigue) at 68 mg. There have been 2 confirmed partial responses: fluoropyrimide-refractory colon cancer (for 12 cycles) and cervical cancer (for 6 cycles). The half-life, Cmax and AUC of RO4929097 all significantly decreased on day 10 compared to day 3, with an increase in clearance for all doses. The half-life was significantly shorter in dose level 3 (p=0.0012) and dose level 4 (p=0.0126) compared to dose level 1. Conclusions: RO4929097 plus cape was well tolerated. Activity was seen in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. However, all plasma concentrations of RO4929097 were above those needed for Notch inhibition (1.9 ng/mL based on prior studies). Dose level 1 (cape 1000 mg/m2 BID and RO4929097 20 mg daily) is the recommended phase II dose. [Table: see text]
PREDICTING RISK FACTORS FOR PERMANENT PACEMAKER PLACEMENT FOLLOWING TRANSCATHETER AORTIC VALVE REPLACEMENT: A UTHEALTH EXPERIENCE
Authors: Ijeoma Ananaba Ekeruo, Omar Hadidi, Yelin Zhao, Richard Smalling, Biswajit Kar, Pranav Loyalka, Daniel Ocazionez, Prakash Balan
Journal: Journal of the American College of Cardiology (2017)
IMPACT OF HOSPITAL OWNERSHIP ON IN-PATIENT MORTALITY AND COST OF HOSPITALIZATION IN PATIENTS ADMITTED FOR HEART FAILURE: INSIGHT FROM THE NATIONAL INPATIENT SAMPLE (NIS)
Authors: Emmanuel Akintoye, Alexandros Briasoulis, Vwaire Orhurhu, Walid Ibrahim, Kartik Kumar, Hala Nas, Jarrett Weinberger
Journal: Journal of the American College of Cardiology (2017)
Phase II feasibility trial of induction chemotherapy (ICT) followed by extrapleural pneumonectomy (EPP) and postoperative radiotherapy (PORT) for cT3N1M0 or less malignant pleural mesothelioma (MPM) (EORTC 08031)
Authors: P. E. Van Schil, P. Baas, R. Gaafar, A. P. Maat, M. van de Pol, B. Hasan, H. M. Klomp, A. M. Abdelrahman, J. Welch, J. Van Meerbeeck
Journal: Journal of Clinical Oncology (2009)

7509 Background: MPM is a highly lethal disease and the role of EPP in the treatment of early stage, potentially resectable MPM remains controversial. EORTC 08031 phase II trial investigated the feasibility of trimodality therapy (TMT) consisting of ICT followed by EPP and PORT. Methods: Eligibility criteria were cT3N1M0 or less, proven MPM, &lt; 70 years, PS 0–1, fit for TMT. ICT consisted of 3 courses of cisplatin 75mg/m 2 and pemetrexed 500mg/m 2 q3weeks. Non-progressing patients (pts) underwent EPP followed by PORT (54Gy, 30 fractions). Primary endpoint was “success of treatment” defined as a patient receiving the full protocol treatment, still alive 90 days after end of treatment without progression and without grade (G) 3–4 toxicity. Using a one step Fleming design 52 patients and 26 successes were required. Secondary endpoints were toxicity of TMT, overall and progression-free survival. Results: 59 pts were registered between 07/26/05 and 08/24/07, 1 was ineligible. Median age was 57 years (range 26–67), M/F 46/12, all proven MPM (31 epithelial, 18 mixed, 9 other). All pts underwent mediastinoscopy, cT1/T2/T3: 36/16/6, cN0/N1: 57/1. 55 pts received 3 cycles of ICT. G3–4 toxicity related to ICT was rare. 46 pts (79%) were operated, 42 (74%) had EPP. R0/1/2: 30/10/3, 6 were re-operated, pT0/1/2/3/4: 2/5/19/15/4, pN0/1/2/3: 34/2/6/2, 90-day mortality: 3 pts (6.5%); in 38 pts (83%) postoperative complications occurred. PORT was initiated in 38 pts and completed in 37 (65%). After PORT 2 pts (3.5%) died due to infection. Persisting G3/4 toxicity after 90 days: 3 pts (5.3%) due to radiation pneumonitis and bronchopleural fistula. After median follow- up of 19.3 months (mos) median overall survival time was 18.4 mos (95% CI 14.8-NR) and median progression-free survival was 13.9 mos (95% CI 10.9–17.1). Only 24 pts (42%) met the definition of success (one-sided 90% CI 0.36–1.00). Conclusions: EORTC 08031 investigated the feasibility of TMT in pts with proven MPM. Due to the low proportion of “successes” this TMT is not considered to be feasible. Although overall results were similar to other series, adjustments to this TMT are necessary. No significant financial relationships to disclose.
Evaluation of the Pharmacokinetics, Immunogenicity, and Safety of XmAb®2513 in the Ongoing Study XmAb2513-01: A Phase 1 Study of Every Other Week XmAb2513 to Evaluate the Safety, Tolerability, and Pharmacokinetics in Patients with Hodgkin Lymphoma or Anaplastic Large Cell Lymphoma
Authors: Anas Younes, Jonathan Zalevsky, Kristie A. Blum, Mitchell R Smith, Henry C. Fung, David A Ramies, Chris E Lawrence, Daniel Combs, Jeffrey Bloss
Journal: Blood (2008)
CRD: A Phase 1 Dose Escalation Study to Determine the Maximum Tolerated Dose of Cyclophosphamide in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Myeloma
Authors: Stephen Schey, Gareth J Morgan, Karthik Ramasamy, Beth Hazel, Karen Phekoo, Sophie Corderoy, Matthew Jenner, Faith Davies
Journal: Blood (2008)
ONE-YEAR MORTALITY INCREASED IN PATIENTS WITH PERI-PROCEDURAL MYOCARDIAL INFARCTION: INSIGHTS FROM THE CHAMPION TRIALS
Authors: Christoph Olivier, Vandana Sundaram, Victoria Ding, Lingyao Yang, Sergio Leonardi, Renato Lopes, Deepak Bhatt, Gregg Stone, Philippe Steg, C. Michael Gibson, Christian Hamm, Matthew Price, Harvey White, Manisha Desai, Robert Harrington, Donald R. Lynch, Kenneth Mahaffey
Journal: Journal of the American College of Cardiology (2017)
Characterization of New Aberrations in 25 Splenic Marginal Zone B-Cell Lymphomas (SMZBCL) Using Spectral Karyotyping Technique (SKY).
Authors: C. Baro, L. Astier, M. Salido, B. Espinet, A. Domingo, I. Granada, D. Costa, J.M. Hernandez, L. Florensa, A. Salar, S. Serrano, F. Sole
Journal: Blood (2005)
COMPARISON OF TRIPLE ANTITHROMBOTIC THERAPY TO TICAGRELOR-BASED DUAL ANTIPLATELET THERAPY FOR LEFT VENTRICLE DYSFUNCTION FOLLOWING STEMI USING NATURAL RANDOMIZATION: A RETROSPECTIVE PILOT STUDY
Authors: Brian J. Potter, Alexandra Bastiany, Fady El-Turaby, Alexandre Angers-Goulet, Alexis Matteau, Samer Mansour, Benoit Daneault
Journal: Journal of the American College of Cardiology (2017)
Randomized intergroup trial of first line treatment for patients &lt;=60 years with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL) with a CHOP-like regimen with or without the anti-CD20 antibody rituximab -early stopping after the first interim analysis
Authors: M. G. Pfreundschuh, L. Trümper, D. Ma, A. Österborg, R. Pettengell, M. Trneny, L. Shepherd, J. Waleswski, P.-L. Zinzani, M. Loeffler
Journal: Journal of Clinical Oncology (2004)

6500 Background: While rituximab improved outcome in elderly patients with DLBCL (Coiffier et al., 2002), there is no data for young low-risk patients. Methods: In a randomized study conducted in 18 countries, untreated patients (18–60 years) with low-risk DLBCL (IPI 0 or 1, stages II-IV and stage I with bulk) were randomized to 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2 given on days 1, 22, 43, 64, 85, and 106 (R-CHEMO). Radiotherapy was planned to initial bulk and/or extranodal involvement. The primary endpoint was time to treatment failure (TTF) with events defined as failure to achieve complete remission, progressive disease, relapse, or death. The trial was powered to show a 10% difference in TTF rate after 3 years. Results: Between 05/2000 and 10/2003, 824 patients were recruited. The first planned interim analysis was performed on 326 evaluable patients with confirmed CD20 positive DLBCL (median age 48 years; IPI=1: 56%, 24% stage III/IV disease, 32% elevated LDH, 50% bulk). Toxicity was not different in the two arms. R-CHEMO patients had a significantly longer TTF (p=0.00003; log rank test) and overall survival (p=0.0057; log rank test) than CHEMO pateints. At a median observation time of 15 months, TTF rates were 84.0% for R-CHEMO and 62.5% for CHEMO. R-CHEMO patients had a higher complete remission rate (84.7% vs. 66.0%; p=0.0003) and a lower rate of progressive disease (6.3% vs. 17.7%; p=0.0039). As the empirical p-value of the log rank test statistic for TTF was considerably lower than the critical value for the interim analysis (pcrit=0.00105), the formal criterion for stopping the trial was met. Therefore, the DSMB recommended the early termination of the treatment phase of the trial in 12/2003 with 45/824 patients still under chemotherapy. Conclusions: The results of the MInT trial indicate that the addition of rituximab to 6 cycles of a CHOP-like regimen significantly improves TTF, CR rates, and OS in young patients with low-risk DLBCL. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche, Basel (Switzerland) Roche, Basel (Switzerland)
Construction of Small‐Diameter Vascular Graft by Shape‐Memory and Self‐Rolling Bacterial Cellulose Membrane
Authors: Ying Li, Kai Jiang, Jian Feng, Jinzhe Liu, Rong Huang, Zhaojun Chen, Junchuan Yang, Zhaohe Dai, Yong Chen, Nuoxin Wang, Wenjin Zhang, Wenfu Zheng, Guang Yang, Xingyu Jiang
Journal: Advanced Healthcare Materials (2017)

Bacterial cellulose (BC) membranes with shape-memory properties allow the rapid preparation of artificial small-diameter blood vessels when combined with microfluidics-based patterning with multiple types of cells. Lyophilization of a wet multilayered rolled BC tube endows it with memory to recover its tubular shape after unrolling. The unrolling of the BC tube yields a flat membrane, and subsequent patterning with endothelial cells, smooth muscle cells, and fibroblast cells is carried out by microfluidics. The cell-laden BC membrane is then rerolled into a multilayered tube. The different cells constituting multiple layers on the tubular wall can imitate blood vessels in vitro. The BC tubes (2 mm) without cell modification, when implanted into the carotid artery of a rabbit, maintain thrombus-free patency 21 d after implantation. This study provides a novel strategy for the rapid construction of multilayered small-diameter BC tubes which may be further developed for potential applications as artificial blood vessels.
APABETALONE (RVX-208) LOWERS CARDIOVASCULAR DISEASE (CVD) IN DIABETES MELLITUS BY A MECHANISM INVOLVING MICROBIOME MEDIATED ACTIVITY ON THE COMPLEMENT PATHWAY
Authors: Norman C. Wong, Ewelina Kulikowski, Cyrus Calosing, Laura Tsujikawa, Sylwia Wasiak, Dean Gilham, Christopher Halliday, Jan Johansson, Michael Sweeney
Journal: Journal of the American College of Cardiology (2017)