tbuckley/cabot-search huggingface dataset:
Antitumor activity of inhibiting SYK kinase with TAK-659, an investigational agent, in DLBCL models.
Authors: Jessica Huck, Rachael Brake, Steve Tirrell, Helen He, Matthew Theisen, Jie Yu, Mengkun Zhang, Suresh Balani, Josephine Atienza, Patrick Vincent, Mark Manfredi, Jonathan Zalevsky, Karuppiah Kannan
Journal: Journal of Clinical Oncology (2014)

8580 Background: Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is a common member of various signal transduction cascades in cells of the hematopoietic lineage including those involved in B-cell receptor (BCR) activation, B cell migration, and B cell polarization. Abnormal SYK activation has been implicated in several hematopoietic malignancies including chronic lymphocytic leukemia (CLL), peripheral T-cell lymphoma (PTCL) and diffuse large B-cell lymphoma (DLBCL). Methods: TAK-659 is an investigational inhibitor of SYK that is currently being evaluated in a Phase I clinical trial (NCT02000934). Results: TAK-659 inhibits SYK with an IC50 of 3.2nM and has the ability to inhibit cellular proliferation in relevant models with an EC50 between 25 to 400nM. Daily oral administration of 60 mg/kg TAK-659 showed anti-tumor activity in DLBCL cell-line xenograft models representing ABC (OCI-LY-10 (TGI 50%), HBL-1 (TGI 40%) and a primary human tumor xenograft model, PHTX-95L (TGI 70%), GCB (OCI-LY-19 (TGI 37%) and non-ABC/GCB (WSU (TGI 50%)) subtypes. Interestingly, in the OCI-LY-19 GCB-type DLBCL model, 60 mg/kg TAK-659 (TGI 37%) showed increased activity over a BTK inhibitor (TGI 15%) suggesting the hypothesis that inhibition of BCR signaling upstream of BTK could be beneficial in treating a broader range of sub-types of B-cell malignancies. The time course of pSYK (pSYK525) and pBLNK (pBLNK65) expression were assessed following single doses of TAK-659. Time dependent inhibition of these phospho-proteins and also increase in expression of cleaved caspase 3, an apoptosis marker was observed in the DLBCL models studied here. Phenotypic assessment of 15 primary DLBCL samples for pSYK and other relevant pathway markers revealed that SYK activation occurs in a considerable number of molecularly heterogeneous DLBCL samples and is consistently associated with activation of the BCR pathway. Conclusions: These results together suggest that SYK activation occurs in various subsets of DLBCL samples and TAK-659 showed activity in pre-clinical models of the various subtypes of DLBCL supporting its clinical investigation in DLBCL patients.
Comparison of six cycles of epirubicin and paclitaxel (ET) versus four cycles of epirubicin and cyclophosphamide, followed by four cycles of paclitaxel (EC-T) as adjuvant therapy for operable breast cancer in women with positive axillary nodes.
Authors: Peng Yuan, Jiayu Wang, Fei Ma, Ying Fan, Yang Luo, Ruigang Cai, Pin Zhang, Qing Li, Binghe Xu
Journal: Journal of Clinical Oncology (2014)

1042 Background: To determine if 6 cycles of ET has similar efficacy to 4 cycles of EC followed by 4 cycles of T, but with shorter treatment time and reduced toxicity. Methods: Patients with operable breast cancer and positive lymph nodes were enrolled and randomized to receive ET (75/175 mg/m2 X 6 every 21 days) or EC (90/600 mg/m2 X 4 every 21 days) followed by T (175 mg/m2 X4 every 14 days). The primary end point was DFS. The trial was designed to detect the upper limits of the 95% confidence interval of the hazard ratio of ET versus an EC-T < 1.30. A sample size of 905 patients was required to detect the difference (a=0.05, β=80%). Assuming a drop-out rate of 10%, 996 patients were required. The first analysis of DFS was planned at the time when 50% of patients were enrolled. Results: Between August 2009 and October 2013, 496 patients were enrolled in the study and 445 patients completed the study treatment protocol, among which 214 patients were in the EC-T arm and 231 patients were in the ET arm. The patient characteristics were well-matched between the two arms. The median age was 49 years in both groups. Of the patients in the EC-T and ET arms, 87.4% and 92.2% were ER/PR-positive, respectively. After a median follow-up of 35.5 months, 28 events were observed (14 each in both arms). The 4-year DFS was 91.3% in the EC-T arm and 91.4% in the ET arm (log-rank p= 0.719,HR = 0.873, 95%CI = 0.416-1.832). Both regimens were well-tolerated. Of the patients in the EC-T and ET groups, 92.1% and 88.7%, respectively, completed all treatment cycles per protocol. Dose reductions were required in 24.8% and 35.5% of the patients in the EC-T and ET arms, respectively. The most frequent grade 3 / 4 toxicities were neutropenia, nausea, and anemia, with no significant difference between the two regimens. Conclusions: The toxicity from six cycles of ET were similar to eight cycles of EC-T in patients with node-positive early breast cancer. The efficacy of the two chemotherapy regimens should await the enrollment of additional patients and a longer follow-up. Clinical trial information: NCT01134523.
Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity
Authors: Rajesh Jayachandran, Aleksandra Gumienny, Beatrice Bolinger, Sebastian Ruehl, Mathias Jakob Lang, Geoffrey Fucile, Saumyabrata Mazumder, Vincent Tchang, Anne-Kathrin Woischnig, Michael Stiess, Gabriele Kunz, Beatrice Claudi, Mathias Schmaler, Kerstin Siegmund, Jianping Li, Simone Dertschnig, George Holländer, Eva Medina, Urs Karrer, Despina Moshous, Dirk Bumann, Nina Khanna, Simona W. Rossi, Jean Pieters
Journal: Immunity (2019)
David Oliver: Falling immigration could destroy the NHS
Authors: David Oliver
Journal: BMJ (2019)

Workforce gaps currently pose a major threat to the viability of our health services, as noted in a joint 2018 report by the King’s Fund, Nuffield Trust, and Health Foundation.1

One in 11 NHS clinical posts is currently unfilled, rising to one in eight nursing posts.2 The report estimates that, without concerted action, the current shortage of NHS staff employed by trusts in England—already around 100 000—will grow to an estimated 250 000 by 2030.

Some of the proposed solutions have been put forward before, by organisations including NHS Providers3 and the Royal College of Physicians.4 These centre on training more staff at home and doing more to look after staff so that more of them stay in the workforce. But this will take years, so …
NCCN Guidelines Insights: Small Cell Lung Cancer, Version 2.2018
Authors: Gregory P. Kalemkerian, Billy W. Loo, Wallace Akerley, Albert Attia, Michael Bassetti, Yanis Boumber, Roy Decker, M. Chris Dobelbower, Afshin Dowlati, Robert J. Downey, Charles Florsheim, Apar Kishor P. Ganti, John C. Grecula, Matthew A. Gubens, Christine L. Hann, James A. Hayman, Rebecca Suk Heist, Marianna Koczywas, Robert E. Merritt, Nisha Mohindra, Julian Molina, Cesar A. Moran, Daniel Morgensztern, Saraswati Pokharel, David C. Portnoy, Deborah Rhodes, Chad Rusthoven, Jacob Sands, Rafael Santana-Davila, Charles C. Williams, Karin G. Hoffmann, Miranda Hughes
Journal: Journal of the National Comprehensive Cancer Network (2018)

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on “Signs and Symptoms of SCLC” and “Principles of Pathologic Review.”
CML leukemic stem cell (CML LSC): Its existence in patients who achieved cytogenetic/molecular response under treatment of TKI.
Authors: Osman Ilhan, Atilla Uslu, Selami Kocak Toprak, Pervin Topcuoglu, Erden Atilla, Pinar Ataca, Aydin Ozturk, Klara Dalva, Onder Arslan, Muhit Ozcan
Journal: Journal of Clinical Oncology (2015)

e18055 Background: Although patients achieve complete cytogenetic response (CCyR) under tyrosine kinase inhibitors (TKIs) in Chronic MyeloidLeukemia (CML), bcr-abl gene positive cells can still be detected. Late treatment failures may be observed related to persistence of leukemic stem cell (LSC). We aimed to present the existence of CML LSC and their clinical impact in CML chronic phase (CP) patients who receives first generation or second generation TKI. Methods: Patient characteristics were as shown in Table 1. With the preference of the clinician, bone marrow (n = 8, 2 new case and 6 under treatment) or peripheral blood samples (n = 7, 5 new cases and 2 under treatment) were drawn. 100 microliters samples were incubated with 10 microliters of IL-1 receptor accesory protein (IL-1 RAcP) (RD, USA) and treated with CD38, CD45 and CD 34 (BD, USA) according to the procedure. Data gathered with Navios device (BC, USA) and analysed with Kalua software. C34 positive cells were selected and existence of IL-1 RAcP on those cells whether carry or or not the expression of CD3 were studied. Results: 7 Of the 8 cases who were under treatment in CCyR and major molecular response (MMR) had the CML-LSC number median 4 (0-27). One of the peripheral blood drawn patients under 400 mg/per day imatinib therapy, has lost MMR with CML-LSC number of 0. Patient who received 2. generation TKI had 2 CML-LSC and clinically there was no difference in the progress of disease (Table 1). Conclusions: Although the limited number of the patients have included in our study, we clearly stated that TKI usage for the treatment of CML could not-eradicate CML-LSC presence although achieving cytogenetic/molecular response. In our opinion, cellular therapy in addition to TKIs will improve patient outcomes in the future. Patient characteristics and summary of CML-LSC numbers. Patient Characteristics (n = 15)1 Median Age (years) 50 (25-79) 1.TKI/2.TKI (n) 7/1 The median number of LSC 1x106 (2x105-1x106) The median number of CML-LSC (n = 15) 4 (0-35) The median number of CML-LSC in patients who are already under treatment (n = 8) 3 (0-27) The median number of CML-LSC in patients with newly diagnosed (n = 7) 8 (1-35) 1All treated patients are in CP with CCyR
Molecular characterization of an extensive lung cancer patient-derived xenograft (PDX) resource.
Authors: Philip C. Mack, Carol J. Bult, Neal Goodwin, Susan D. Airhart, Rebekah Burich, Clifford Tepper, Primo Lara, Edison T. Liu, David R. Gandara
Journal: Journal of Clinical Oncology (2014)

8025 Background: A large series of non-small cell lung cancer (NSCLC) PDX models has been established through direct implantation of patient tumor material into immune compromised mice. Here we report the molecular characterization of this resource, reflecting the biologic diversity and heterogeneity inherent to NSCLC with implications for drug development. Methods: Patient tumor acquired from biopsy, resection or pleural effusion was implanted subcutaneously into the flank of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. The contributing patient tumor (PT) and the resultant PDX were analyzed for driver mutations (Response Genetics Inc., and Illumina TSCAP); copy number variants (CNV) and global RNA expression (Affymetrix arrays). Normalized gene expression across all PDX models was analyzed using Principal Component Analysis (PCA). Clustering was performed based on shared patterns of gene expression, analyzed using Gene Set Enrichment Analysis to identify biological themes. Results: At time of submission, 55 NSCLC models from 53 patients were fully established & characterized. Contributing patients: Median age 62 (36-82); 62% female; 22% stage IV; 32 adenocarcinoma, 19 squamous cell carcinoma (SCC), 2 large cell. All driver mutations detected in PTs were retained in resultant PDXs: 10 EGFR, 11 KRAS, 1 ALK, 1 NRAS. PCA revealed 6 clusters with subgroups differentiated by genes associated with signal transduction, epithelial-mesenchymal transition and DNA repair. SCC models predominantly populated two clusters, with one group almost exclusively comprised of PI3KCA amplified models with upregulated/amplified FGFR1-3 signaling components. KRAS mutants showed divergent cluster patterns, with several models grouping with EGFR/ALK mutants, potentially influenced by PI3K mutation status. Conclusions: The UC Davis Cancer Center/The Jackson Laboratory NSCLC PDX resource is one of the largest, most characterized collections currently in use for advanced therapeutic development. PCA subgrouping, along with mutation and CNV status, suggest strategies to refine patient selection and treatment algorithms.
Retrospective analysis of toxicity in patients (pts) with liver metastases (mets) from phase 3 studies of trastuzumab emtansine (T-DM1) in pts with metastatic breast cancer (MBC).
Authors: David Miles, Hans Wildiers, Nadia Harbeck, Marjorie C. Green, Meghna Samant, Mark D. Pegram
Journal: Journal of Clinical Oncology (2014)

609 Background: In two phase 3 studies in pts with HER2-positive MBC, treatment with the antibody–drug conjugate T-DM1 resulted in increased progression-free survival (PFS) and overall survival (EMILIA) and PFS (TH3RESA) v control arms. T-DM1 is associated with grade (gr) ≥3 elevations of hepatic transaminases. We examined the association between the presence of liver mets at baseline (with/without abnormal transaminases) and toxicity, as well as efficacy in pts from these 2 studies. Methods: EMILIA and TH3RESA data were analyzed separately. Analyses included the rates of any grade adverse events (AEs), gr ≥3 AEs (including AEs identified with hepatotoxicity), selected AEs of interest for T-DM1, ORR, and PFS. Comparisons were pts with/without liver mets at baseline in the absence or presence of abnormal (>1× upper limit of normal [ULN]) alanine aminotransferase (ALT). Results: Overall, the rate of gr ≥3 AEs was lower with T-DM1 v controls (Table). In pts with liver mets and elevated ALT at baseline, the incidence of gr ≥3 AEs was higher with T-DM1, with the highest incidence in the “investigations” category, which includes laboratory data such as increased transaminases (EMILIA, 18.2% v 0%; TH3RESA, 17.4% v 10.5%). Reduction in risk of progression with T-DM1 was similar in all subgroups and comparable with the overall randomized populations (Table). Conclusions: This retrospective analysis suggests that in the presence of liver mets (with/without elevated ALT at baseline), the clinical efficacy benefit of T-DM1 is maintained. The AEs observed with T-DM1 in pts with liver mets and elevated ALT were primarily laboratory-based. Clinical trial information: NCT00829166 and NCT01419197. All pts No liver mets Liver mets Liver mets/ ALT ≤1 × ULN Liver mets/ ALT >1 × ULN T-DM1 Control T-DM1 Control T-DM1 Control T-DM1 Control T-DM1 Control EMILIA N 495 496 311 304 176 178 142 148 33 28 Any gr ≥3 AEs, %* 41 57 42 61 49 57 45 57 64 54 PFS HR (95% CI) 0.65 0.55–0.77 0.73 0.60–0.88 0.62 0.48–0.81 0.62 0.46–0.83 0.41 0.21–0.82 TH3RESA N 404 198 241 123 163 75 117 56 46 19 Any gr ≥3 AEs, %* 32 44 30 40 35 49 29 53 50 37 PFS HR (95% CI) 0.53 0.42–0.66 0.54 0.40–0.72 0.51 0.36–0.73 0.48 0.31–0.75 0.56 0.28–1.13 * Pts who received ≥1 dose of study drug.
Abstract 9916: Potent Antithrombotic Effect of a Small-molecule, Reversible and Direct Inhibitor of Factor XIa With Minimum Bleeding Time Effect In Rabbit Models of Arterial Thrombosis and Hemostasis
Authors: Pancras C Wong, Mimi Quan, Carol Watson, Earl Crain, Ruth Wexler, Dietmar Seiffert
Journal: Circulation (2013)

BMS-654457 ((+) 3’-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5’-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid). is a potent, reversible and direct factor XIa (FXIa) inhibitor. It inhibits human FXIa with K i of 0.2 nM and with &gt;1000 fold selectivity over most of the relevant serine proteases. We conducted an in vivo proof of concept study and characterized the antithrombotic and bleeding time (BT) effects of BMS-654457 in rabbits. The direct thrombin inhibitor melagatran was included as a reference agent. BMS-654457 and melagatran were studied in rabbit models of electrically-induced carotid arterial thrombosis and cuticle bleeding. Compounds were given as an IV bolus plus infusion 30 min or IV infusion 60 min before the initiation of thrombosis or cuticle transection. Integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of the antithrombotic effect. Ex vivo clotting times were measured by using a commercial hemostasis analyzer. BMS-654457 at 0.011+0.008, 0.037+0.027, 0.11+0.08, 0.37+0.27 and 1.1+0.8 mg/kg+mg/kg/h IV increased iCBF to 17±3, 46±6*, 48±9*, 87±10* and 96±5%*, respectively, vs . 16 ± 3% in the vehicle-treated group (n=6 per group, *P&lt;0.05, vs . vehicle). The antithrombotic EC 50 (concentration that increased iCBF by 50% of the control, μM) was 0.28 for BMS-654457 and 0.15 for melagatran. At their top equivalent antithrombotic doses, BMS-654457 and melagatran increased BT by 1.33±0.08 and 6.7±0.3-fold, respectively (n=6 per group). As expected for a FXIa inhibitor, BMS-654457 increased ex vivo activated partial thromboplastin time (aPTT) without changing prothrombin time and thrombin time. The antithrombotic effect of BMS-654457 was significantly correlated with its ex vivo aPTT, supporting ex vivo aPTT as a pharmacodynamic biomarker. This study demonstrated that BMS-654457 is as effective as melagatran in the prevention of arterial thrombosis in rabbits, and prolonged BT less than melagatran. These findings suggest that inhibition of FXIa, with a small-molecule, reversible and direct inhibitor, may represent a promising antithrombotic therapy with a wide therapeutic index.
Potential life years saved using ado-trastuzumab emtansine (T-DM1) in second-line HER2-positive metastatic breast cancer.
Authors: Mark D. Danese, Marc Halperin, Anthony Masaquel, Oyewale O. Abidoye
Journal: Journal of Clinical Oncology (2014)

e17686 Background: T-DM1 was approved for HER2+ metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane. The EMILIA trial results versus lapatinib + capecitabine (L+C) showed a significant difference in median overall survival (Verma, 2012; 5.8 month difference). We projected the potential life years (LY) saved by using T-DM1 in women with HER2+ MBC receiving second-line HER2-targeted therapy in the United States (US). Methods: Using US Census estimates and SEER cancer registry incidence data, we projected counts of women with HER2+ MBC in the 15-years from 2013-2027 and accounted for de novo stage IV, metastatic recurrences, and adjuvant trastuzumab use. Based on CLEOPATRA trial data, we estimated that 53% of first-line treated women would receive HER2-targeted second-line therapy. Mean survival was estimated using flexible parametric survival models to extrapolate the EMILIA overall survival results for T-DM1 vs. L+C (44.8 vs. 35.6 months). Overall survival was attenuated in women ≥75 years to account for competing risks. Results were reported for 2 scenarios: all patients treated with T-DM1, and all patients treated with L+C. Monte Carlo methods were used to generate uncertainty intervals (UI) for the results. Sensitivity analyses examined T-DM1 compared with published survival data for tastuzumab + capecitabine (T+C) and trastuzumab + lapatinib (T+L). Results: In our model, 2,674 women were estimated to be eligible for and receive second-line HER2-targeted therapy in 2013. If treated with L+C as second-line therapy, these women were projected to accrue 7,604 LY after initiating therapy. If treated with T-DM1 instead, these women were projected to accrue 9,597 LY, an incremental benefit of 1,993 LY saved. Over a 15-year period, the cumulative LY saved from using T-DM1 instead of L+C was projected to be 30,254 (95% UI 25,220-35,515). The incremental LY saved by using T-DM1 instead of T+C was 35,681 (95% UI 21,993-44,215) and instead of T+L was 73,002 (95% UI 66,103-78,959). Conclusions: The use of T-DM1 could increase the years of life lived in women with HER2+ MBC substantially. The results depend on the survival estimates for the specific alternative regimens.
Effects of a 12-week home-based exercise program on quality of life, psychological health, and the level of physical activity in colorectal cancer survivors.
Authors: Ji Young Kim, MI KYUNG LEE, Ji-Hee Min, Dong Hoon Lee, Sunghyun Hong, Junga Lee, Ji-Hye Park, Dong-il Kim, Sanghui Chu, Nam Kyu Kim, Justin Y Jeon
Journal: Journal of Clinical Oncology (2014)

9630 Background: Although the importance of physical activity (PA) and exercise has been recognized, there are few randomized controlled trials which investigated the effects of exercise on psychological health of colorectal cancer survivors. Therefore, the purpose of this study is to examine the effects of home-based exercise program on quality of life (QOL), psychological health, and the level of PA in colorectal cancer survivors. Methods: One hundred twenty three colorectal cancer survivors were randomized into either home-based exercise (Intervention) group or control group. The home-based exercise program included unsupervised walking, stationary bike, or swimming for aerobic exercise and providence of resistance exercise DVD, pedometer, and exercise logs. QOL was measured by the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) scale. The 7 Day physical activity recall (PAR) was used to assess the level of physical activity. In addition, the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale and Patient Health Questionnaire (PHQ) were administered. All assessments were conducted at baseline and 12 week. Results: Ninety nine participants completed the trial (80.5%). Both QOL and fatigue improved in the intervention group (QOL p-value =.020; fatigue p-value =.022), while they did not change in the control group (QOL p-value =.395; fatigue p-value =.265). The change in QOL and fatigue between intervention and control group was not statistically. The level of PA was significantly increased at 12-week in the intervention group, and the change was significantly different from the control group (p-value=.004). Conclusions: The 12-week home-based exercise program improves the QOL and psychological health in colorectal cancer survivors. In addition, we have demonstrated that home-based exercise program was effective to increase level of physical activity in stage II–III colorectal cancer survivors. This study was supported by the National Research Foundation of Korea (2013K2A1A2054437) and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1120230).