tbuckley/cabot-search huggingface dataset:
ABT-869, a novel multi-target receptor tyrosine kinase inhibitor (RTKI), combined with chemotherapy is synergistic in the therapy of acute myeloid leukemia cells with FLT3-ITD mutation (FLT3-AML)
Authors: J. Zhou, M. Pan, S. Loh, Z. Xie, Y. Lim, M. Lilly, K. Glaser, D. Albert, S. Davidsen, C. S. Chen
Journal: Journal of Clinical Oncology (2006)

13064 Background: Internal tandem duplications (ITDs) of fms-like tyrosine kinase 3 (FLT3) receptor are identified in 20–25% of adult AML patients associated with poor prognosis. ABT-869 is active in FLT3-AML and is currently under clinical investigaton. We hypothesize that the combination of ABT-869 with chemotherapy can improve the therapeutic index in FLT3-AML. Methods: Using Calcusyn software, the additive, synergistic or antagonistic effect of ABT-869 with concurrent or sequential cytosine arabinoside (Ara-C) or doxorubicin (Dox) was measured in MV4–11 and MOLM-14 cells. The synergistic combination sequence was further tested in a MV4–11 xenograft model in four groups (10 mice/group) including control, Ara-C, ABT-869, and combination (Ara-C first for 4 days, then daily ABT-869). Cell cycle analysis and apoptosis and signal pathway assays were performed in vitro and in vivo. Results: ABT-869 induced dose- and time-dependent apoptosis on FLT3-AML cells resulting in down regulation of p-FLT3, p-STAT5, Bcl-X L and up regulation of p53 and BID. ABT-869 caused G 1 -phase arrest and the removal of cells in the S- and G 2 /M-phase mediated by reduction of cyclins D and E. We observed significant synergistic effect with Ara-C or Dox first, followed by ABT-869, as well as in concurrent treatment with ABT-869 and Dox. Simultaneous treatment with ABT-869 and Ara-C only achieved additive effect. Conversely, we found an antagonistic effect in the sequence of pretreatment of ABT-869 followed by chemotherapy. In a MV4–11 xenograft model, all mice succumbed to leukemia in the control and Ara-C groups (median survival = 53 and 55.5 days respectively). Combination therapy gave a faster reduction of tumor volume compared to ABT-869 treatment alone (p=0.03) without recurrence of leukemia in either group by day 67. In vivo immunohistochemistry (IHC) analysis revealed ABT-869 potently inhibited VEGF and phosphor-ERK. Conclusions: ABT-869 can be given after Ara-C or Dox to act synergistically. Our study suggests that combinations of RTKIs with chemotherapy should be carefully tested prior to clinical protocol development. A clinical trial of such combination therapy in FLT3-AML is warranted. No significant financial relationships to disclose.
Incidence of airflow limitation in subjects 65–100 years of age
Authors: Johannes A. Luoto, Sölve Elmståhl, Per Wollmer, Mats Pihlsgård
Journal: European Respiratory Journal (2015)

The true incidence of chronic obstructive pulmonary disease is largely unknown, because the few longitudinal studies performed have used diagnostic criteria no longer recommended by either the European Respiratory Society or the American Thoracic Society (ATS). We studied the incidence and significance of airflow limitation in a population-based geriatric sample using both an age-dependent predicted lower limit of normal (LLN) value and a fixed-ratio spirometric criterion. Out of 2025 subjects with acceptable spirometry at baseline, 984 subjects aged 65–100 years completed a 6-year follow-up visit. Smoking habits were registered at baseline. Exclusion criteria were non-acceptable spirometry performance according to ATS criteria and inability to communicate. Airflow limitation was defined both according to forced expiratory volume in 1 s (FEV 1 )/forced vital capacity ratio &lt;0.7 and &lt;LLN. The incidence of airflow limitation per 1000 person-years was 28.2 using a fixed ratio and 11.7 with LLN, corresponding to a 1.41-fold higher incidence rate using a fixed ratio. The incidence increased dramatically with age when using a fixed ratio, but less so when using LLN. In addition, a sex effect was observed with the LLN criterion. LLN airflow limitation was associated with increased 5-year mortality. Presence of fixed-ratio airflow limitation in individuals classified by LLN as non-obstructive was not associated with increased mortality.
Assessment of <i>EGFR</i> Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)
Authors: Chris Karlovich, Jonathan W. Goldman, Jong-Mu Sun, Elaina Mann, Lecia V. Sequist, Krzysztof Konopa, Wei Wen, Philipp Angenendt, Leora Horn, David Spigel, Jean-Charles Soria, Benjamin Solomon, D. Ross Camidge, Shirish Gadgeel, Cloud Paweletz, Lin Wu, Sean Chien, Patrick O'Donnell, Shannon Matheny, Darrin Despain, Lindsey Rolfe, Mitch Raponi, Andrew R. Allen, Keunchil Park, Heather Wakelee
Journal: Clinical Cancer Research (2016)

Abstract Purpose: The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors. Experimental Design: Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing. Results: The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P &amp;lt; 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 – 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 – 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response. Conclusions: These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386–95. ©2016 AACR.
Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment
Authors: I. D. Davis, B. Brady, M. Millward, B. K. Skrumsager, U. Mouritzen, P. E. Kristjansen, G. McArthur
Journal: Journal of Clinical Oncology (2007)

3055 Background: rIL-21 is a pleiotropic class I cytokine that activates CD8 + T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual. [Table: see text]
Former ministers call for commission to review NHS and social care funding
Authors: Gareth Iacobucci
Journal: BMJ (2016)

Three former health ministers have called for a cross party commission to be established to review future funding of the NHS and social care in England.

The proposal by the Liberal Democrat former health minister Norman Lamb has been backed by the former Conservative health secretary Stephen Dorrell and the former Labour health secretary Alan Milburn.

The trio warned that health services could collapse without radical change and investment that required cross party cooperation.

Speaking to parliament on 6 January, Lamb argued that the extra £8bn (€10.9bn; $11.7bn) in NHS funding by 2020 pledged by the government was not enough to tackle huge hospital deficits and …
OECD rates quality of UK healthcare as worse than in many similar countries
Authors: Nigel Hawkes
Journal: BMJ (2015)

Access to healthcare in the United Kingdom is good, but the quality of care is not so good, shows the latest digest of statistics from the Organisation for Economic Co-operation and Development.1 The UK’s health spending remains lower than in similar developed economies and is below the OECD average.

Health at a Glance is an annual publication that brings together a mass of statistics from 34 OECD member countries and 10 partner countries. This year’s edition, which is based chiefly on 2013 statistics, finds the UK ranked near average for most outcomes measured—but, given that the OECD 34 includes several less developed nations such as Turkey and the former Eastern Bloc countries, this is not as satisfactory as it might appear.

Against …
Continuous MEK inhibition by AZD6244 (ARRY-142886) results in exhaustion of the cutaneous keratinocytic stem cell pool and resembles senescence driven skin aging
Authors: K. Schad, K. Baumann Conzett, V. Enderlin, M. V. Cantarini, M. Nief, L. French, R. Dummer
Journal: Journal of Clinical Oncology (2008)

9075 Background: The Raf/MEK/ERK signaling pathway is constitutively activated in melanoma. AZD6244 blocks MEK1/2, inhibiting ERK phosphorylation, and is associated with cutaneous toxicities similar to EGF targeting molecules but can also induce depigmentation. Methods: 28 patients (pts) with unresectable melanoma stage III/IV were randomized to temozolomide (TMZ 200mg/m2) or AZD6244 (100 mg po bid). 13 pts received AZD6244 initially, and 9 pts AZD6244 following tumor progression with TMZ. Acute and chronic skin reactions were documented and lesion biopsies were compared to matched controls in normal skin. Immunohistochemistry (p53, Ki67, pancytokeratin) was performed. Results: 19/22 (86,3%) AZD6244-treated pts presented with cutaneous eruptions. 17 pts (77,2%) developed acute papulopustular rash in seborrhoic regions within the first treatment weeks. Chronic skin changes (> 6–8 weeks) included xerosis, paronychia and pulpitis sicca, which is similar to that observed with EGFR-inhibition. In addition, we observed hair depigmentation and vitiligo correlating with the AZD6244 treatment period. Hair abnormalities such as nonscarring alopecia, trichomegaly of the eyebrows, facial hypertrichosis and thinning of the hair as seen with EGFR-Inhibitors were not observed. Histology of acute skin lesions revealed apoptotic keratinocytes (p53 positive) and destruction of the adnexal structures by neutrophilic infiltrates, reduced expression of cytokeratins and a shift of the proliferation (Ki67) from basal to the suprabasal keratinocytes reflecting self amplifying cells. Chronic lesions revealed a reduced stratum corneum, thinning of the epidermal cell layers with apoptotic keratinocytes and focal infiltrates mainly of neutrophils and occasional lymphocytes. The number of melanocytes was not reduced. Conclusions: The clinical presentation of AZD6244 associated skin reactions partly overlaps with those observed upon EGFR-Inhibition. Additionally melanocytic function is affected. We postulate that continuous MEK inhibition by AZD6244 results in exhaustion of the cutaneous keratinocytic stem cell pool thus resembling skin senescence. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca Oncology
Abstract #4606: Bazedoxifene (TSE-424) is a potent inhibitor of long-term estrogen deprived breast cancer cells
Authors: Joan Lewis-Wambi, Helen Kim, V. Craig Jordan
Journal: Cancer Research (2009)

Estrogen deprivation by use of aromatase inhibitors is very effective in the treatment of hormone-responsive breast cancers, however, acquired resistance inevitable develops. We have previously reported the development of a long-term estrogen deprived breast cancer cell line, MCF-7:5C, which is resistant to estrogen withdrawal but undergoes apoptosis in the presence of physiologic concentrations of estradiol through activation of the mitochondrial death pathway. At present, however, it is not known whether MCF-7:5C cells respond to selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4OHT), GW5638, raloxifene (ral), EM-652 (acolbifene) or bazedoxifene. We therefore determined the effects of the above mentioned SERMs on the growth of MCF-7:5C cells and examined whether these compounds are able to block the apoptotic effects of estradiol in these cells. We found that bazedoxifene and EM-652 dramatically reduced the growth of MCF-7:5C cells wheras 4OHT, ral, and GW5638 had no effect on the growth of these cells. Bazedoxifene at 1 \#956;M inhibited the growth of MCF-7:5C cells by more than 80% whereas EM-652 inhibited the growth by ~50%. Interestingly, EM-652 at 10 nM was able to completely reverse the apoptotic effect of 1 nM estradiol in MCF-7:5C cells. The pure antiestrogen fulvestrant also inhibited the growth of MCF-7:5C cells by ~50-60% and this compound was able to partially reverse the apoptotic effect of estradiol. Western blot analysis revealed that bazedoxifene completely downregulated estrogen receptor alpha (ER\#945;) protein expression but it significantly increased cyclin A and cyclin D1 expression in these cells. In contrast, EM-652 and fulvestrant completely inhibited ER\#945;, cyclin D1, and cyclin A protein expression. Overall, these results show that long-term estrogen deprivation alters the response of breast cancer cells to SERMs and that bazedoxifene and fulvestrant might be effective treatment options in these resistant cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4606.
HG-13 * SOX9 AS A DOWN-STREAM TARGET IN RAS/MEK-DRIVEN PEDIATRIC GLIOMA
Authors: H. Sabelstrom, R. Jandial, K. Shchors, S. Masic, A. Ho, S. Vandenberg, T. P. Nicolaides, K. Nguyen, S. Yakovenko, M. D. Prados, C. D. James, M. S. Berger, G. I. Evan, E. Y. Snyder, W. A. Weiss, A. I. Persson
Journal: Neuro-Oncology (2015)

Reference EPFL-CONF-214231View record in Web of Science Record created on 2015-12-02, modified on 2017-05-25
Unilateral Axillary Toxic Erythema of Chemotherapy in a Patient With Previous Axillary Lymph Node Dissection
Authors: Alyssa Yeager, Sasha Stephen, Amy Forrestel, Misha Rosenbach
Journal: JAMA Dermatology (2016)

alprostadil.Alprostadil exerts a vasodilator, antiplatelet, and cytoprotective effect; it is an inhibitor of smooth muscle proliferation and fibrinolytic activity.Potential adverse events can occur, including fever, flushing, hypotension, hypocalcemia, and apnea.Prostanoids have also been used in patients with peripheral arterial disease (PAD) in association with revascularization to relieve pain or improve ulcer healing. 5Prostanoids are probably not as effective in treating PAD because this conditions it is not an alteration of microcirculation as in livedoid vasculitis and SS.In venous ulcers, PGE-1 has also been described to be effective. 6 We describe the successful treatment of a case of SS with alprostadil.This drug induces immediate pain relief, complete healing, and prevention of new skin ulcers.Alprostadil may be a therapeutic alternative for other dermatological conditions secondary to obstructive vasculopathy of cutaneous microcirculation.
Characterization of concurrent ovarian and endometrial carcinoma by copy-number analysis (CNA) and gene expression profiling (GEP)
Authors: A. Guirguis, E. Elishaev, K. Timms, J. Reid, V. Abkevich, A. Gutin, J. Launchbury, K. Zorn, D. Deloia
Journal: Journal of Clinical Oncology (2007)

10546 Background: Coexistence of endometrioid carcinoma at both sites, the ovary and the endometrium, is between 10–30%. Current staging relies on clinical and pathologic assessment, which is not quantitative and highly subjective. The objective of this study was to evaluate archived tissues from patients with concurrent tumors for CNA and GEP, and determine if either or both of these techniques could be used to define the primary site of the endometroid carcinoma. Methods: A gynecologic pathologist confirmed that all specimens from both sites were of endometrioid histology; grades I/II. CNA was determined by extracting DNA from both disease and non-disease tissues for hybridization to the Affymetrix 500K SNP microarrays. Illumina HumanRef8 BeadChip microarrays were used throughout to obtain GEP for 7 endometrial and 7 ovarian primary stage I tumor samples. Differentially expressed genes between both groups created a corresponding discrimination scores (DS). The performance of the discrimination scores were evaluated by the Leave-One-Out method. In a similar fashion, a test set of 16 tumor samples from patients with concurrent tumors were profiled. The prediction of these tumors’ origin based on the DS were compared with pathological assessment and copy number analysis. Results: Concurrent tumors display more copy number changes than singular tumors of either tissue, with a greater fraction of the genome involved. Analysis of the non-affected tissue assists in identifying tumor-specific changes. We identified a set of 30 differentially expressed genes between both ovarian and endometrial tumors that discriminates a tumors’ origin with about 80% confidence. For patients with concurrent tumors, comparison of their origin based on GEP, CNA, and pathological assessment shows limited concordance. Conclusion: Shared somatic copy number changes in simultaneous endometrioid carcinomas of the ovary and endometrium indicate a common origin and hence metastasis. For these relatively common concurrent tumors, clinical inferences based on CNA appear more robust than those based on GEP, and more objective than pathological assessment. No significant financial relationships to disclose.
Chemoradiotherapy (CRT) after chemotherapy (CT) improves survival for locally-advanced (LA) pancreatic cancer patients: Retrospective analysis of 181 patients enrolled in prospective phases II and III GERCOR studies
Authors: F. Huguet, T. André, P. Hammel, P. Artru, J. Balosso, P. Ruszniewski, E. Touboul, A. de Gramont, C. Louvet
Journal: Journal of Clinical Oncology (2005)

4095
A proposal for a novel system to evaluate and approve anti-cancer drugs
Authors: H. M. Guirgis
Journal: Journal of Clinical Oncology (2008)

14666 Background: Background: Response rates to cancer therapy do not necessarily correlate with improved overall survival (S). Orphan drugs status ensures a fast track in approving anti-cancer drugs. We propose a scoring system (NASAe) to integrate Newness (N), Administration (A), S and Adverse effects (Ae) for approval and evaluation. Methods: Relative weights were given to each parameter. Data on OS of approved drugs and criteria for Ae were utilized. N gets 4 for a new concept, genomics or a class of drugs, 2: a new drug of the same class or a new combination, 1: advantageous drug and 0 for “ me too drug‘. Oral administration (A) gets 2, injections 1 and infusions >4 hours 0. Prolongation of mOS by < 7days (d), 7–15;> 15–30d, >1–4 months (m), >4–12, and > 12 m get 0; 2; 4; 6; 8; 10 respectively. Ae similar to placebo get 4, Grades (gr) 1; 3, gr 2; 2, gr 3; 1 and gr 4;0. Results: The total scores (TS: NASAe: 4+2+10+4) were 20 &100% and awarded to WBZ-4, should it meet its projected expectations in GISTs. Imatinib scored 4+2+10+2, TS being 18 and 90%. Sorafenib for HCC prolonged mOS by 84 d, TS being (2+2+6+2),12 and 60%. The mOS of RCC patients treated by Sorafenib was not reached, placebo being 14.7 m. The projected TS was (2+2+>6+2),>12 and >60%. Erlotinib and gemcitabine improved the mOS of patients with advanced pancreatic carcinoma by >10 d. TS was (2+1+2+1), 6 and 30%. Bortezomib increased the mOS in relapsed multiple myeloma by 6 m. TS was (4+1+8+1),14 and 70%. Drugs might be up- or down- graded as data emerges. Conclusions: Over 40 drugs and combinations have been evaluated and will be presented. The system requires further validation. No significant financial relationships to disclose.
Clinical and Hematologic Studies With 1-β-&lt;sc&gt;D&lt;/sc&gt;-Arabinosylcytosine&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Papac, Rose J.
Journal: JNCI Journal of the National Cancer Institute (1968)

Journal Article Clinical and Hematologic Studies With 1-β-D-Arabinosylcytosine Get access Rose J. Papac, M.D. Rose J. Papac, M.D. Department of Internal Medicine, Yale University School of Medicine, New Haven, and Veterans Administration Hospital, West Haven, Connecticut 06510 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 40, Issue 5, May 1968, Pages 997–1002, https://doi.org/10.1093/jnci/40.5.997 Published: 01 May 1968 Article history Received: 18 October 1967 Accepted: 10 January 1968 Published: 01 May 1968