tbuckley/cabot-search huggingface dataset:
Randomized phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Ann Sing Lee, Benny C.Y. Zee, Foon Yiu Cheung, Philip Kwong, Ashley Chi Kin Cheng, Maria Lai, Chloe Kwok, Marc Chong, Jacques Jolivet, C L Chiang, K C Leung, Steven Siu, Conrad Lee, Stewart Yuk Tung
Journal: Journal of Clinical Oncology (2012)

4105 Background: XIAP inhibits caspases which are proteases responsible for apoptotic cell death. It is highly expressed in HCC. AEG35156 is a second generation antisense oligonucleotide targeting XIAP mRNA, thus lowers the apoptotic threshold of cancer cells. It also accumulates in the liver. This study is designed to assess the added benefit of combining AEG35156 with sorafenib. Methods: Patients with histologically or clinically diagnosed (AASLD criteria) HCC who had failed or were unsuitable for resection or ablative therapies were randomized (2:1) to receive either weekly injection of AEG35156 300mg in combination with sorefanib 400mg BID or sorefanib alone. The primary end point was progression-free survival (PFS). Other endpoints were overall survival (OS), response rates and safety. Results: 51 patients were recruited. 48 patents were evaluable. There were 31 patients in the combination arm and 17 in the control arm. The median age was 60. 88% of patients were male. 81% of patients were hepatitis B carrier. 90% of patients belong to Child-Pugh class A. The median follow-up was 16.2 months. The PFS for the combination arm was 4.0 months (95% CI: 1.2-4.1) and 2.6 months for control arm. The OS for the combination arm was 6.5 months (95% CI: 3.9-11.5) and 5.4 months for the control arm. There were 3 partial responders (Choi’s criteria) in the combination arm (10%, 95% CI: 3-27%) and none (0%) in the control arm. Patients who had the study treatment interrupted (PFS 4.0, 95% CI: 2.4-5.4) or had dose modification (PFS 4.45, 95% CI: 1.0-6.5) according to protocol did significantly better than those who had no dose reduction (PFS 1.2, 95% CI: 1.2-4.0) and those in the control arm (PFS 2.6, 95% CI: 1.2-5.4). This also applies to OS. Regarding toxicities, there were one AEG35156 related serious adverse event (SAE) of hypersensitivity and two sorafenib related gastrointestinal SAE. Conclusions: AEG35156 in combination with Sorafenib was well tolerated in patients with advanced HCC. Dose reduced AEG35156 in combination with sorafenib have shown more activity than sorafenib alone and warrants further investigation.
Survival with short-course EOX chemotherapy for advanced gastroesophageal cancer.
Authors: Olusola Olusesan Faluyi, Abdul Qayum, Helen Wong, Helen Neville-Webbe, Michael Marcus, Adrian Moss
Journal: Journal of Clinical Oncology (2014)

e15067 Background: Advanced gastroesophageal malignancies are associated with significant morbidity and a median survival of less than a year. Platinum containing regimens (such as the epirubicin, oxaliplatin and capecitabine [EOX] regimen) remain the standard of care in the first line setting. Furthermore, the survival benefit of second line chemotherapy is emerging. Patients were permitted up to 8 cycles of EOX in the Real-2 trial but managed only a median of 6 cycles due to toxicity. Methods: We retrospectively studied the benefit of short course EOX chemotherapy in a frailer patient population managed at a major Cancer Centre in North West England. We reviewed the outcome for 95 patients with gastroesophageal cancer (PS 0-2, 94% adenocarcinoma) who were treated with an initial course of 4 cycles of EOX over a two year period (Jan 2009 – Dec 2010). Patients who had disease progression more than 3 months after completion of 4 cycles of EOX received up to 4 more cycles. 88.4% of patients had died at the time of analysis and the survival outcome was compared with those who were allowed long course EOX in the Real-2 study. Results: Patients received a median of 3 cycles in their initial course of EOX. For the patients with locally advanced disease (n=16), median survival was 15.0 months (CI: 0 – 30.9 months) compared with 14 months in the Real-2 study. For those with metastatic disease (n = 79), median survival was 7.0 months (CI: 5.5 – 8.5 months) compared with 9.3 months in the Real-2 study. Conclusions: In this retrospective study, within the limits of comparison with historical controls from a clinical trial, there was no observed detriment to survival from receiving short course EOX chemotherapy in patients with locally advanced disease. However, short course EOX may have been associated with reduced survival in patients with metastatic disease. In summary, we provide some preliminary data on the outcome with short course EOX chemotherapy for patients with gastroesophageal cancer at a major cancer centre. A randomized trial of short course compared with long course EOX chemotherapy on a larger number of patients is required. Such should incorporate quality of life studies to put any possible benefit of the longer course of EOX treatment in perspective.
Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial
Authors: Francois-xavier Mahon, Johan Richter, Joelle Guilhot, Henrik Hjorth-Hansen, Antonio Almeida, Jeroen J.W.M. JWM Janssen, Jiri Mayer, Kimmo Porkka, Panayiotis Panayiotidis, Ulla Stromberg, Marc G Berger, Joanna Diamond, Hans Ehrencrona, Veli Kairisto, Katerina Machova Polakova, Martin C. Mueller, Satu Mustjoki, Andreas Hochhaus, Markus Pfirrmann, Susanne Saussele
Journal: Blood (2016)
Prognostic significance of chromogranin A in small pancreatic neuroendocrine tumors.
Authors: Mustafa Raoof, Zeljka Jutric, Laleh Golkar Melstrom, Susanne Warner, Yanghee Woo, Yuman Fong, Gagandeep Singh
Journal: Journal of Clinical Oncology (2017)

375 Background: Theincidence of non-functional pancreatic neuroendocrine tumors (PNETs) &lt; 2 cm is rising. The biologic behavior of these tumors is variable and therefore their management remains controversial. We hypothesized that chromogranin A (CgA) levels are prognostic in these patients and may help guide management. Methods: Patients with PNETs measuring &lt; 2 cm, without distant metastases were identified from the National Cancer Database (NCDB) over a ten-year period (2004-2014). Patients were categorized as CgA high (&gt; 36.4 ng/ml) or CgA low (&lt;36.4 ng/ml), and those lacking data on CgA levels were excluded from the study. Univariate and multivariate analyses were performed using Cox proportional hazards model. Results: Of the 445 eligible patients, 149 (33.5%) were CgA Low and 296 (66.5%) were CgA High. Median CgA level was 71 (Inter-quartile range, IQR 24-294) ng/ml. On multivariate analysis, CgA levels independently predicted overall survival after controlling for tumor size, grade, clinical nodal status and academic status of the facility (p = 0.001). At a median follow up of 26.5 months there were no deaths in the CgA Low group whereas 8% of the patients in CgA High group had died (p = 0.0068). Only CgA High patients benefited from surgical resection (HR 0.31, 95% CI 0.11-0.86, p = 0.025). Conclusions: Serum CgA levels can be incorporated in surgical decision making for patients with small PNETs. Patients with a high CgA should be strongly considered for resection.
Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective
Authors: Patricia A. Cowper, Shubin Sheng, Renato D. Lopes, Kevin J. Anstrom, Judith A. Stafford, Linda Davidson-Ray, Sana M. Al-Khatib, Jack Ansell, Paul Dorian, Steen Husted, John J. V. McMurray, P. Gabriel Steg, John H. Alexander, Lars Wallentin, Christopher B. Granger, Daniel B. Mark
Journal: JAMA Cardiology (2017)

The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds. To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation, we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial.To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system.This economic analysis uses patient-level resource use and clinical data collected in the ARISTOTLE trial, a multinational randomized clinical trial that observed 18 201 patients (3417 US patients) for a median of 1.8 years between 2006 and 2011.Apixaban therapy vs warfarin therapy.Within-trial resource use and cost were compared between treatments, using externally derived US cost weights. Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population. Quality-of-life adjustment factors were obtained from external sources. Cost-effectiveness (incremental cost per quality-adjusted life-year gained) was evaluated from a US perspective, and extensive sensitivity analyses were performed.Of the 3417 US patients enrolled in ARISTOTLE, the mean (SD) age was 71 (10) years; 2329 (68.2%) were male and 3264 (95.5%) were white. After 2 years of anticoagulation therapy, health care costs (excluding the study drug) of patients treated with apixaban therapy and warfarin therapy were not statistically different (difference, -$60; 95% CI, -$2728 to $2608). Life expectancy, modeled from ARISTOTLE outcomes, was significantly longer with apixaban therapy vs warfarin therapy (7.94 vs 7.54 quality-adjusted life years). The incremental cost, including cost of anticoagulant and monitoring, of achieving these benefits was within accepted US norms ($53 925 per quality-adjusted life year, with 98% likelihood of meeting a $100 000 willingness-to-pay threshold). Results were generally consistent when model assumptions were varied, with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon.Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness.clinicaltrials.gov Identifier: NCT00412984.
Axl/phosphatidylinositol 3-kinase signaling inhibits mineral deposition by vascular smooth muscle cells. Collett GD, Sage AP, Kirton JP, Alexander MY, Gilmore AP, Canfield AE. Circ Res. 2007 Mar 2;100(4):502-9. Epub 2007 Jan 25.
Authors: Collett Gd, Sage Ap, Kirton Jp, Alexander My, Gilmore Ap, A E Canfield
Journal: Circulation Research (2007)
Quality-of-life findings in patients with midgut neuroendocrine tumors: Results of the NETTER-1 phase III trial.
Authors: Jonathan R. Strosberg, Edward M. Wolin, Beth Chasen, Matthew H. Kulke, David L Bushnell, Martyn E. Caplin, Richard P. Baum, Pamela L. Kunz, Timothy J. Hobday, Andrew Eugene Hendifar, Kjell E. Oberg, Maribel Lopera Sierra, Dik J. Kwekkeboom, Philippe B. Ruszniewski, Eric Krenning
Journal: Journal of Clinical Oncology (2017)

348 Background: Neuroendocrine tumor progression is associated with decline in quality of life, both due to tumor and hormone-related symptoms. The Phase III NETTER-1 trial randomized patients with advanced, progressive midgut NETs to receive treatment with 177 Lu-DOTATATE ( 177 Lu; Lutathera) versus high-dose (60 mg) Octreotide LAR (Oct). EORTC questionnaires C30 and GINET21 were assessed during the trial in order to determine the impact of treatment on health-related quality of life (HRQoL). Methods: Patients completed EORTC QLQ-30 and QLQ-G.I.NET21 questionnaires at baseline and every 12 weeks thereafter until disease progression. Raw scores were converted to a 100-point scale and individual changes from baseline scores were assessed. Clinically relevant ( ≥ 10 point) deterioration/improvement was considered clinically significant. Results: Clinically and statistically significant improvements in QoL were observed in the 177 Lu arm versus the Oct arm at certain time points in key domains of HRQoL including global health status and diarrhea. In mean, global health status improved in 28% of patients on 177 Lu arm vs. 15% on Oct, and worsened in 18% of patients on 177 Lu vs. 26% on Oct. Diarrhea improved in 39% of patients on 177 Lu vs. 23% on Oct, and worsened in 19% of patients on 177 Lu vs. 23% on Oct. There was a trend towards improvement in pain that was not statistically significant. Flushing appeared to improve compared to baseline in both arms of the study with no clear advantage to treatment with 177 Lu vs. Oct. Conclusions: QoL analysis suggests benefit in important domains associated with 177 Lu treatment compared to high-dose octreotide in patients with advanced midgut NETs, and confirms the treatment value of 177 Lu on patient QoL, in addition to the meaningful increase in progression-free survival already reported. Clinical trial information: NCT01578239.
Effect of dexrazoxane on doxorubicin-induced testicular toxicity.
Authors: Irit Ben-Aharon, Moran Tzabari, Naftaly Savion, Ruth Shalgi, Salomon M. Stemmer
Journal: Journal of Clinical Oncology (2012)

2556 Background: Seminal advances in anti-cancer therapy result in growing numbers of young male cancer survivors for whom treatment-induced infertility represents a major late-term concern. Doxorubicin (DXR) has been previously shown to exert toxic effect on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we aimed to study its potential effect to reduce DXR-induced testicular toxicity. Methods: Male mice were injected intraperitoneally with 5mg/kg DXR or 100mg/kg DEX or the combination of both and scarified at one month post treatment. Saline-injected mice served as controls. Testes were excised, weighed and further processed. For oxidative stress determination glutathione assay was performed on testes' lysates and P38 protein levels were determined by western blot analysis. Bax levels were used to assess apoptosis. Immunohistochemistry and confocal microscopy were used to study the effect of DXR, DEX and their combination, on the testis histology as well as on the spermatogonial reserve. Results: One month after DEX and DXR treatment, a striking decline in testicular weight was observed (decrease by 60% compared with control values; decrease of 54% in DXR-only treated mice; p&lt;0.05). DEX prevented DXR-induced oxidative stress. However, DEX enhanced DXR-induced apoptosis within the testes and furthermore, the combination depleted the spermatogonial reserve one month after treatment. Conclusions: DEX activity in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR may exacerbate DXR-induced testicular toxicity.
Histologic classification and grading enhances gallbladder cancer staging: A population-based prognostic score validated by the U.S. Extrahepatic Biliary Malignancy Consortium.
Authors: Thuy Tran, Cecilia Grace Ethun, Timothy M. Pawlik, Stefan Buettner, Kamran Idrees, Chelsea A Isom, Ryan C. Fields, Bradley Krasnick, Sharon M. Weber, Ahmed Salem, Robert C. G. Martin, Charles Raben Scoggins, Perry Shen, Harveshp Mogal, Carl Richard Schmidt, Eliza W Beal, Ioannis Hatzaras, Rivfka Shenoy, Shishir Kumar Maithel, George A. Poultsides
Journal: Journal of Clinical Oncology (2017)

356 Background: Beyond the most common adenocarcinoma type, several gallbladder cancer (GBC) histologies have been described as being associated with more favorable (papillary) or less favorable outcome (adenosquamous, mucinous, signet ring). We sought to examine the added value of histologic type and grade on the existing AJCC staging system for resected GBC. Methods: Patients who underwent resection of GBC from 1988-2013 were identified using the Surveillance Epidemiology End Results (SEER) registry. A prognostic score was created by assigning points for T stage, N stage, grade and histology based on the regression coefficient in multivariate analysis. The score was externally validated using the US Extrahepatic Biliary Malignancy Consortium (USEBMC) database (2000-2015) and compared with the AJCC staging system. Results: Of 7,915 patients identified in SEER, 83% had adenocarcinoma, 7% papillary, 4% adenosquamous, 4% mucinous, and 2% signet ring. In the USEBMC database, the frequencies of the respective histologies were 86, 9, 2, 1 and 2%. Median survival per histologic type, for SEER and USEBMC respectively, were 45 and 110 mos for papillary, 16 and 24 mos for adenocarcinoma, 14 and 12mos for mucinous, 8 and 4mos for adenosquamous, and 9 and 15mos for signet ring (P between histologies &lt; 0.001 for both cohorts). On multivariate analysis, T stage, N stage, grade and histology were independent predictors of survival. The developed prognostic score, based on points for each of these 4 variables, showed excellent discriminatory ability both in the SEER and USEBMC cohorts. The AUC for the prognostic score was significantly improved compared with the AJCC system (0.69 vs. 0.64,both P &lt; 0.001 using SEER, and 0.76 vs. 0.66,both P &lt; 0.001 using USEBMC). Conclusions: The incorporation of histology and grade into the TNM system allows for a simple and accurate tool to determine prognosis following resection of GBC. [Table: see text]
A phase II study of nimotuzumab and CDDP concurrent with radiation in locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Wan-Teck Lim, Mei-Kim Ang, Quan Sing Ng, Lan-Ying Wang, Noan-Minh Chau, Daniel S. W. Tan, Wen Yee Chay, Swan Leong, Eng-Huat Tan
Journal: Journal of Clinical Oncology (2012)

e16024 Background: Nimotuzumab is a humanized monoclonal antibody (MAb) to EGFR. Concurrent cisplatin with radical radiotherapy (RT) is standard treatment for locally advanced SCCHN where it is unresectable or for organ-preservation. We explored the combination of nimotuzumab with concurrent CDDP and RT in these patients (pts). Methods: Pts with locally advanced stage III/IV SCCHN were eligible for study if: age &gt; 18, ECOG 0-1, SCC, normal organ function. Analysis was by intention-to-treat (ITT). CDDP 100 mg/m 2 on days 1, 22, and 43 was given with RT (70 Gy over 35 fractions). Nimotuzumab was given as a flat dose of 200 mg weekly on weeks 1 to 8 of treatment. Pts were followed up for RECIST response, progression free survival and toxicity. Results: Twenty-eight pts were available for analysis at the time of report. The median age was 58 (30-69). Most were Chinese (90%) and all ECOG 0-1. Twelve pts had oropharynx Ca, 16 had non-oropharyx Ca. Twenty-five pts were evaluable for response, 2 pts withdrew consent after 2 weeks, 1 pt died of undiagnosed Fanconi anemia. By ITT, the best overall response rate (CR/PR) was 78.6% (12 CR/10 PR), SD 3.6% (1), PD 7.2% (2). Pts with oropharynx Ca had higher PFS rate at 1 year than non-oropharynx (80% vs 48%). Major grade 3/4 toxicities were limited to mucositis, dysphagia, and fatigue. Grade 5 toxicity due to febrile pancytopenia occurred in 1 pt with undiagnosed Fanconi’s. Acneiform rash typical of EGFR inhibitors occurred in 1 pt. Conclusions: Nimotuzumab with concurrent CDDP/RT is feasible and there was minimal additional toxicity encountered. Final results will be updated at the meeting.
Simultaneous, quantitative detection of multiple biomarkers in human breast cancers using multicolor nanoparticles
Authors: A. H. Al-Hajj, M. V. Yezhelyev, T. Liu, R. M. O’Regan
Journal: Journal of Clinical Oncology (2006)

619 Background: Conventional methods of detecting breast cancer biomarkers are hampered by a lack of adequate quantification and/or an inability to detect multiple targets on small quantities of tissue. We have previously demonstrated that estrogen receptor (ER), progesterone receptor (PR) and HER2/neu (HER2) can be detected and quantified simultaneously using antibodies (Abs) directly conjugated to nanoparticles, called quantum dots (QDs), on single breast cancer sections (ASCO 2005). We have expanded our assay to use multicolored QDs conjugated directly to Abs (QD-Abs) to detect and quantify simultaneously ER, PR, and HER2, along with 3 putative biomarkers, epidermal growth factor receptor (EGFR), mammalian target of Rapamycin (mTOR), and insulin-like growth factor receptor (IGFR), in breast cancer cell lines and human breast cancers. Methods: We used multicolored QDs directly conjugated to primary Abs to detect the 6 proteins in breast cancer cell lines (MCF-7, BT474, MDA-231) and single sections of human breast cancers. The 6 proteins were quantified using spectral separation microscopy, and compared to Western blotting. Results: We detected all 6 proteins simultaneously using QD-Abs in breast cancer cell lines and breast tumors. Using hyper-spectral imaging and wavelength-resolved spectroscopy, we separated all 6 fluorescent signals, and quantified the expression of each protein detected using QD-Abs. Quantification of the biomarkers showed good correlation with Western blotting. Conclusions: These results are proof of principle that 6 proteins can be simultaneously quantified using QD-Abs in single breast cancer sections. The use of multiplex QDs offers a novel method of determining the proteome of an individual breast cancer on single breast cancer sections. With the expanding use of targeted therapies in breast cancer, the ability to detect multiple proteins on small breast cancer specimens using QD-Abs, could allow not only the accurate selection of therapy, but a unique method of determining the activity of specific targeted agents. No significant financial relationships to disclose.
Post-Allogeneic Monitoring with Molecular Markers Detected by Pre-Transplant Next Generation Sequencing (NGS) Predicts Clinical Relapse in Patients with Chronic Myelomonocytic Leukemia (CMML)
Authors: Nicolaus Kröger, Thomas Schroeder, Tatjana Zabelina, Anita Badbaran, Ulrike Bacher, Guido Kobbe, Susanne Schnittger, Alexander Kohlmann, Torsten Haferlach
Journal: Blood (2012)