tbuckley/cabot-search huggingface dataset:
The incidence of BCR-ABL mutations in patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) treated with nilotinib or imatinib in ENESTnd: 24-month follow-up.
Authors: G. Saglio, H. Kantarjian, J. Reiffers, S. Jootar, M. E. Kalaycio, H. Shibayama, X. Fan, N. J. Gallagher, Y. Shou, R. A. Larson, T. P. Hughes, A. Hochhaus
Journal: Journal of Clinical Oncology (2011)

6502 Background: In ENESTnd, nilotinib has demonstrated superior efficacy vs imatinib in newly diagnosed CML-CP pts. Baseline (BL) BCR-ABL mutation status and emergence of new mutations with minimum 24 month (mo) follow-up are reported here. Methods: CML-CP pts received nilotinib 300 mg bid (n = 282), nilotinib 400 mg bid (n = 281), or imatinib 400 mg qd (n = 283). Mutation testing was performed by direct sequencing of the kinase domain in a central laboratory at: BL, 5-fold increase in PCR levels, < MMR at 12 mo, loss of MMR, or treatment end. Results: No pt (N = 846) had a mutation at BL. Twice as many new mutations occurred on imatinib vs nilotinib and were more frequent in pts with High or Intermediate Sokal risk. A similar number of pts had new mutations on nilotinib 300 (4%) and 400 mg bid (3%), with a similar mutation profile. Emergence of T315I mutations and the number of pts with multiple mutations was similar across arms. Majority of mutations on imatinib were nilotinib-sensitive (imatinib-resistant). Seven of 20 pts with new mutations on imatinib progressed to AP/BC on treatment and of the 13 pts who did not progress, all but 2 discontinued due to suboptimal response or treatment failure. Conclusions: The incidence of new mutations was higher on imatinib vs nilotinib, with nilotinib-sensitive (imatinib-resistant) mutations mostly observed in the imatinib arm. More pts with new mutations progressed to AP/BC on imatinib than on nilotinib. N (%) Nilotinib 300 mg bid N = 282 Nilotinib 400 mg bid N = 281 Imatinib 400 mg qd N = 283 Pts with new mutation 10 (4) 8 (3) 20 (7) New mutations by Sokal score Low Int High 1 4 5 1 2 5 1 8 11 Mutation category T315I 3 (1) 2 (< 1) 3 (1) Less sensitive to nilotinib* 5 (2) 6 (2) 4 (1) Sensitive to nilotinib† 2 (< 1) 0 13 (5) Multiple mutations 3 (1) 2 (< 1) 3 (1) Event type Progression to AP/BC** 1 (10) 2 (25) 7 (35) Loss of CCyR** 0 0 0 Loss of MMR** 0 0 3 (15) * Mutations less sensitive to nilotinib: E255K/V, F359C/V, and Y253H. † Mutations sensitive to nilotinib: all mutations except E255K/V, F359C/V, Y253H, and T315I. ** Based only on pts with mutations. Pts who progressed to AP/BC and also lost MMR or CCyR were only counted as progression to AP/BC.
Ex Vivo Generation of CD4+ Th17 Cells to Prevent and Treat Infection from Antibiotic-Resistant Klebsiella Pneumoniae in Immunocompromised Patients
Authors: Pawel Muranski, Manuel Franco-Colon, Dhanalakshmi Chinnasamy, Kong Chen, Scott Stegemann, Jinwen Sui, Sawa Ito, Marianna Sabatino, David F. Stroncek, Tara Palmore, Jay Kolls, A John Barrett
Journal: Blood (2014)
Cytotoxic T Lymphocytes (CTL) Specific for Adenovirus and CMV Can Be Generated from Umbilical Cord Blood for Adoptive Immunotherapy
Authors: Catherine M. Bollard, Patrick Hanley, Conrad Russell Cruz, Ann M. Leen, Jeffrey J. Molldrem, Hao Liu, Adrian P. Gee, Helen E. Heslop, Gianpietro Dotti, Barbara Savoldo, Elizabeth J. Shpall
Journal: Blood (2008)
Towards Personalized Intervention for Alzheimer’s Disease
Authors: Xing Peng, Peiqi Xing, Xiuhui Li, Ying Qian, Fuhai Song, Zhouxian Bai, Guangchun Han, Hongxing Lei
Journal: Genomics Proteomics & Bioinformatics (2016)

Alzheimer's disease (AD) remains to be a grand challenge for the international community despite over a century of exploration. A key factor likely accounting for such a situation is the vast heterogeneity in the disease etiology, which involves very complex and divergent pathways. Therefore, intervention strategies shall be tailored for subgroups of AD patients. Both demographic and in-depth information is needed for patient stratification. The demographic information includes primarily APOE genotype, age, gender, education, environmental exposure, life style, and medical history, whereas in-depth information stems from genome sequencing, brain imaging, peripheral biomarkers, and even functional assays on neurons derived from patient-specific induced pluripotent cells (iPSCs). Comprehensive information collection, better understanding of the disease mechanisms, and diversified strategies of drug development would help with more effective intervention in the foreseeable future.
Interfollicular CD10 Expression and Follicular PD1 Tumor-Infiltrating Lymphocytes As Biologic Risk Factors in Patients with Previously Untreated Follicular Lymphoma Receiving Rituximab-Based Biologic Therapy: An Alliance Correlative Science Study (CALGB 50901, 50402, 50701, 50803, 50401)
Authors: Aliyah R Sohani, Brandy Pitcher, Amy Chadburn, Jonathan W. Said, Peter Martin, Myron S. Czuczman, Nancy L Bartlett, Cara A. Rosenbaum, John P. Leonard, Bruce D. Cheson, Eric D. Hsi
Journal: Blood (2015)
NSAIDs and the failing heart
Authors: Gunnar H Gislason, Christian Torp-Pedersen
Journal: BMJ (2016)

NSAIDs pose a clear risk to some patients and tighter regulation is justified

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs and are mainly used to alleviate pain and inflammation. NSAIDs were first introduced over a century ago and most of the commonly used NSAIDs were registered in an era with few requirements for safety documentation. Therefore, for most of these drugs, there is an alarming lack of randomised studies addressing their safety. With the introduction of selective cyclo-oxygenase (COX) 2 inhibitors, concerns were raised that unbalanced COX 2 inhibition might increase cardiovascular risk.1 This has been demonstrated in several randomised and observational studies, and further warning flags have been raised about the cardiovascular safety of non-selective NSAIDs.2 3 4 5 6 7

Arfe and colleagues8 present results from a nested case-control study based on real world data from four European countries and almost 10 million NSAID …
IL2RA (CD25) Recruits Inhibitory Phosphatases to the Cell Membrane and Mediates Negative Feedback Control of STAT5 Signaling in Acute Lymphoblastic Leukemia
Authors: Huimin Geng, Jae-Woong Lee, Zhengshan Chen, Behzad Kharabi Masouleh, Christian Hurtz, Eugene Park, Gang Xiao, Samir Parekh, Steven M. Kornblau, Ari Melnick, Elisabeth Paietta, Markus Muschen
Journal: Blood (2014)
I.O.I.B.D. Questionnaire on the clinical use of Azathioprine, 6-Mercaptopurine, Cyclosporine-A and Methotrexate in the treatment of I.B.D
Authors: Sgm Meuwissen, K Ewe, MA Gassull, Karel Geboes, D Jewell, F Pallone, D Rachmilewitz, J Rask-Madsen, RH Riddell
Journal: Gut (1996)
Epidémie de rougeole en Suisse en 1997 : conséquences sur l'élimination de la rougeole à l'horizon 2007
Authors: W J Paget, H Zimmermann, H Vorkauf
Journal: Eurosurveillance (2000)

Les cas cliniques de rougeole sont declares, depuis juin 1986, a Sentinella, le Reseau Suisse de Surveillance Sentinelle (Swiss Sentinel Surveillance Network - SSSN) (1) et depuis janvier 1988, les cas d’infections sont rapportees par le systeme de notification national des laboratoires. Ces deux systemes de surveillance forment l’un des outils principaux pour evaluer les activites relatives a la vaccination ROR (rougeole, oreillons et rubeole) en Suisse. La vaccination contre la rougeole est recommandee depuis 1976, et une campagne nationale de vaccination ROR a ete lancee en 1987 par le Comite Consultatif Suisse sur les Vaccinations (Swiss Advisory Board for Immunisation) et l’Office Federal Suisse de Sante Publique (Swiss Federal Office of Public Health, SFOPH). Depuis 1996, deux doses de vaccin ROR sont recommandees pour tous les enfants - une a 15 mois et une avant l’entree a l’ecole (4-7 ans).
CT Based Quantification of Radiation Induced Lung Damage (RILD) and the Interaction with Chemotherapy and Cetuximab
Authors: H. Sharifi, W. van Elmpt, R. Vandendries, A.C. Dingemans, M. Das, G. Nalbantov, M. Oellers, P. Lambin, J. Belderbos, D. De Ruysscher
Journal: Annals of Oncology (2012)
An open-label, single-arm phase II study of everolimus (RAD001) in patients with relapsed/refractory classical Hodgkin lymphoma (HL).
Authors: P. B. Johnston, L. T. Lewis, J. W. Rogerio
Journal: Journal of Clinical Oncology (2010)

TPS299 Background: Overactivation of the PI3K/Akt/mTOR signaling pathway is associated with cell survival and proliferation in lymphomas. It has been demonstrated that the PI3K/Akt/mTOR pathway is constitutively active in HL cell lines. TSC/mTOR signaling has also been demonstrated to activate NF-κB survival signaling in vitro. Constitutively active NF-κB promotes cell survival and proliferation in HL. RAD001 is an oral inhibitor that blocks overactivation of mTOR, part of the PI3K/Akt/mTOR signaling pathway, inhibits constitutive NF-κB survival signaling and downregulates the truncated isoform of transcription factor CCAAT enhancer binding protein in B cell lymphoma and HL cell lines. In a reported phase II study RAD001 10 mg qd was tested in heavily pretreated patients with relapsed or refractory aggressive, indolent, and uncommon lymphomas, including Hodgkin disease. As part of this phase II trial, 16 patients with HL were treated with a median of 6 prior therapies (87.5% had at least one prior stem cell transplant). The ORR at the time of reporting was 42%, all partial remissions. Nine patients had ongoing therapy, 6 patients discontinued due to PD. The median treatment duration at the time of reporting was 6 months (max of 13 months). Thus mTOR inhibition appears a viable target for relapsed/refractory HL given the response in this heavily pretreated population. Methods: The purpose of this phase II multicenter trial is to demonstrate the safety and efficacy of RAD001 10 mg given daily as an oral dose in adult patients with relapsed/refractory classical HL whose disease has progressed following high dose chemotherapy with AHSCT and/or after therapy with a gemcitabine- or vinorelbine- or vinblastine- containing regimen. This phase II study is a Simon optimal 2-stage design. During stage 1, 35 patients will be enrolled. If ≤6 responses are noted, the trial will be terminated. If ≥8 responses are observed, the trial will continue to stage 2 to enroll an additional 33 patients. A total of 68 patients will be enrolled. The primary endpoint is to determine the ORR by PET and CT scans. Secondary endpoints will include safety/tolerability, time to response, DoR, DCR (CR, PR, and SD), PFS, and OS. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Can OS-6 replace PFS-6 as a primary endpoint in phase II studies on glioblastoma patients given antiangiogenetic drugs?
Authors: E. Franceschi, A. A. Brandes, A. Tosoni, A. Bacci, L. Morandi, F. Spagnolli, R. Degli Esposti, S. Bartolini, R. Poggi, M. Ermani
Journal: Journal of Clinical Oncology (2010)

2022 Background: In the last decade, progression-free survival (PFS) at 6 months (PFS-6) has been considered the best endpoint in phase II trials on recurrent glioblastoma (GBM). However, since a new standard of care was established by the EORTC/NCIC phase III trial, no data have reported on the PFS-6 or overall survival (OS) obtained with second line treatment following combined RT/TMZ. Moreover, antiangiogenic agents might alter data on response by repairing the blood-brain barrier and diminishing contrast enhancement, thus precluding the accurate assessment of any reduction in the tumor burden. The issue of a robust primary endpoint for phase II studies is therefore still open. The aim of the study was to evaluate outcome endpoints for second line treatment at recurrence. Methods: A retrospective analysis was made using a database on 653 GBM patients (pts) followed prospectively between 5/2001 and 8/2008. Eligibility criteria: age ≥ 18 years; PS 0-2; histological diagnosis of GBM; cytotoxic treatment at disease progression after RT/TMZ. The log-rank test was used to evaluate the significance of the prognostic variables, and the Cox model to ascertain any association between PFS and OS. Results: 150 pts (median age: 52 years, [24–76 y]) were enrolled. MGMT methylation status, evaluable in 110 pts, was present in 38% of cases. Median OS was 18.5 months. At disease progression, 40 pts (27%) received temozolomide, 92 pts (61%), nitrosourea-based chemotherapy, and 18 pts (12%) other treatments. At the time of recurrence, mPFS was 2.5 months (95%CI: 2.0–3.1), PFS-6 15% (95%CI: 9.5%–21.3%, mOS 7.6 months (95%CI: 6.9–8.3) and OS-6 64% (95%CI: 56.6%–72.2%). In the Cox proportional hazard model, PFS with the second line treatment was correlated with OS measured as from the start of the second line treatment (p < 0.0001). Conclusions: The findings made in the present study, the first in literature to evaluate outcome endpoints for a second line treatment after RT/TMZ in GBM pts, confirm that a PFS-6 of 15% should be considered the cut-off for active cytotoxic drugs in phase II studies on recurrent GBM. For antiangiogenic compounds, OS-6 can be considered as a sound endpoint. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, OncoMethylome Sciences, Roche, Schering-Plough GlaxoSmithKline, Merck Sharp & Dohme, Roche, sanofi-aventis, Schering-Plough
Phase I/II study of MEDI-551, a humanized monoclonal antibody targeting CD19, in subjects with relapsed or refractory advanced B-cell malignancies.
Authors: Trishna Goswami, Andres Forero, Mehdi Hamadani, Anne Sonet, Gregor Verhoef, Michelle A. Fanale, Celeste M. Bello, Wenmei Huang, Bruce D. Cheson
Journal: Journal of Clinical Oncology (2012)

8065 Background: Novel B-cell targeting agents, including monoclonal antibodies such as rituximab, are among recent advances in treatment of B-cell malignancies. New approaches are needed for patients progressing after rituximab-based therapies. MEDI-551 is an afucosylated monoclonal antibody targeting CD-19, a B-cell restricted transmembrane protein with enhanced affinity and antibody-dependent cellular cytotoxicity. Methods: Pts with relapsed or refractory follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, or multiple myeloma received single agent MEDI-551 at dosages ranging from 0.5 mg/kg to 12 mg/kg via intravenous infusion over 28-day cycles; cohorts 1-6 received 0.5, 1, 2, 4, 8, and 12 mg/kg, respectively. Results: 25 pts were enrolled in the phase I portion Jun 2010–Aug 2011. No maximum tolerated dose (MTD) was achieved. Most AEs were grade 1/2 with dose-independent frequency and severity (Table). Six pts had grade 3 toxicities including tumor lysis syndrome, infusion reaction, thrombocytopenia, and neutropenia, or grade 4 neutropenia. No grade 5 AEs were seen. All pts recovered. Three partial responses (PR) and 2 complete responses (CR) were seen in DLBCL and FL pts at 0.5, 4, and 8 mg/kg. Activity included a CR lasting 9 mo. in a FL pt in cohort 1, who is currently being retreated with MEDI-551 on relapse. Conclusions: MEDI-551 demonstrated a safety profile warranting further study and showed no MTD reached at the highest dose studied. Anti-tumor activity is suggested by the responses achieved across dose levels. Phase II is currently enrolling subjects. This study is funded by MedImmune, LLC. [Table: see text]
The Effect Of Prior Chemotherapy Courses With MD-AraC On The Hematopoietic Stem Cell Mobilization
Authors: Ru Feng, Muchen Xie, Yu Zhang, Yongqiang Wei, Fen Huang, Xiaolei Wei, Xiaofang Li, Qi Wei, Min Dai, Qifa Liu, Jing Sun, Zhengshan Yi, Zhongxin Zheng
Journal: Blood (2013)
Molecular and Neural Functions of Rai1 , the Causal Gene for Smith-Magenis Syndrome
Authors: Wei-Hsiang Huang, Casey J. Guenthner, Jin Xu, Tiffany Nguyen, Lindsay A. Schwarz, Alex W. Wilkinson, Or Gozani, Howard Y. Chang, Mehrdad Shamloo, Liqun Luo
Journal: Neuron (2016)
Inequality dynamics in the workplace among microbiologists and infectious disease specialists: a qualitative study in five European countries
Authors: A. Huttner, M. Cacace, L. d’Andrea, C. Skevaki, D. Otelea, F. Pugliese, E. Tacconelli
Journal: Clinical Microbiology and Infection (2016)

To explore the social, cultural, psychological and organizational factors associated with inequality in the workplace among clinical microbiologists (CM) and infectious disease (ID) specialists in European hospitals.We analysed data from 52 interviews and five focus groups involving 82 CM/ID specialists selected from university, research or community hospitals in five countries, one each in Northern, Western, Eastern, Southeastern and Southwestern Europe. The 80 hours of recordings were transcribed, and the anonymous database coding process was cross-checked iteratively by six researchers.Inequality affects all the institutions in all the countries we looked at, denying or reducing access to professional assets with intensity and form that vary largely according to the cultural and organizational context. Discrimination is generally not explicit and uses disrespectful microbehaviours that are hard to respond to when they occur. Inequality affected also loans, distribution of research funds and gender and country representation in boards and conference faculty. Parenthood has a major impact on women's careers, as women are still mainly responsible for family care. Responses to discrimination range from reactive to surrender strategies.Our study offers an effective model for diagnosing discriminatory behaviours in a medical professional setting. Knowledge of inequality's drivers could help national ID/CM societies in collaboration with major European stakeholders to further reduce such discrimination. The effect of discrimination on the quality of healthcare in Europe needs further exploration.
Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome
Authors: Chuansheng Guo, Shujun Xie, Zhexu Chi, Jinhua Zhang, Yangyang Liu, Li Zhang, Mingzhu Zheng, Xue Zhang, Dajing Xia, Yuehai Ke, Linrong Lu, Di Wang
Journal: Immunity (2016)
Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus Adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003)
Authors: M. Yamasaki, T. Yasuda, M. Yano, M. Hirao, K. Kobayashi, K. Fujitani, S. Tamura, Y. Kimura, H. Miyata, M. Motoori, O. Shiraishi, T. Makino, T. Satoh, M. Mori, Y. Doki
Journal: Annals of Oncology (2016)
Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.
Authors: Mark Andrew Dickson, William D. Tap, Mary Louise Keohan, Sandra P. D'Angelo, Mrinal M. Gounder, Ping Chi, Cristina R. Antonescu, Jonathan Landa, Li-Xuan Qin, Dustin D. Rathbone, Yelena Ustoyev, Aimee Marie Crago, Samuel Singer, Gary K. Schwartz, Mercedes M. Condy
Journal: Journal of Clinical Oncology (2013)

10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting &gt; 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.
A single-blind, placebo-controlled, sequential design study evaluating the potential effects of trabectedin on the QT intervals.
Authors: G. M. Manikhas, L. Dirix, J. B. Vermorken, K. Park, M. Jain, R. Thertulien, M. Gonzalez, J. Jiao, T. V. Parekh, A. P. Staddon
Journal: Journal of Clinical Oncology (2010)

e13096 Background: Trabectedin (Tr) is a new class of antitumor agents with a unique mechanism of action, involving the transcription- dependent nucleotide excision repair system. Methods: Enrolled patients (n=75; pts) had locally advanced or metastatic solid tumors who received ≤3 prior lines of chemotherapy and who had relapsed or progressive disease following standard of care treatment with chemotherapy or were intolerant to such therapy. Pts were administered placebo (saline solution, PBO) and Tr (1.3 mg/m2) as 3-h IV infusions on Days (D) 1 and 2, respectively. The primary objective was to assess the potential effects of Tr on the QT/QTc interval. Serial triplicate ECG recordings and time- matched pharmacokinetic (PK) blood samples were collected over 24 hours on D 1 and 2. The QT/QTc was assessed by comparing mean QTc intervals and changes from baseline (ΔQTc), by Fredericia's and Bazett's methods. The difference in ΔQTc between Tr and PBO was calculated at each time point (ΔΔQTc). Noninferiority was to be concluded if the upper limit of all 95% confidence intervals (CI) fell below 10 ms. Results: Tr concentrations in plasma were within the expected range with Cmax occurring near the end of the 3-h infusion. No pts had a QTc that was >500 ms or a time-matched increase from baseline in QTc that >60 ms at any time point. The upper limit of the 1-sided 95% CIs for the ΔΔQTc between Tr and PBO at all time points was <6.65 ms, irrespective of the QT correction method. No PK/PD correlation was apparent based on regression analyses. No adverse events were reported suggestive of proarrhythmic potential. Conclusions: A therapeutic dose of Tr did not prolong the QTc interval in pts with advanced solid tumor malignancies. The safety and PK profile of Tr was similar to that observed in previous studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson Johnson & Johnson