tbuckley/cabot-search huggingface dataset:
Combination statin/metformin and prostate cancer specific mortality: A population-based study.
Authors: Grace L. Lu-Yao, Yong Lin, Dirk Moore, John Graff, Antoinette Stroup, Kimberly McGuigan, Stephen Crystal, Shahla Amin, Kitaw Demissie, Robert S. DiPaola
Journal: Journal of Clinical Oncology (2015)

5018 Background: Obesity and metabolic syndromes (MetS) are associated with an increased risk of prostate cancer mortality. A recent pre-clinical study showed that combination statin /metformin (CSM) was more effective in inhibiting metastasis than standard chemotherapy (docetaxel) with less toxicity in an in vivo model. As clinical data on this topic are limited, this population-based study is to examine the association between treatment with CSM and prostate cancer specific mortality (PCSM) by obesity/MetS status. Methods: SEER-Medicare linked data were used to identify patients with high-risk prostate cancer (stage T3/T4 or PSA>20 or Gleason 8-10) in 2007 – 2009. Prescription drug use was identified from Medicare Part D Event files. Obesity/MetS conditions were identified by the presence of ICD-9 diagnosis codes 278.00, 278.01, or 277.7. Cox proportional hazards models were used to compare PCSM with covariates including demographic characteristics, prognostic factors, and cancer treatment(s) received. Results: This study cohort consisted of 22,110 high-risk prostate cancer patients, of which 1,365 died of prostate cancer by 12/31/2009. Use of CSM was associated with a 43% reduction in PCSM, more pronounced in men with obesity/MetS conditions (Table). The results were similar when we limited the analysis to patients with minimal comorbidity. Conclusions: To our knowledge, this is the largest clinical study to assess the potential effect of CSM on PCSM. CSM or statin use was associated with a large reduction in PCSM, particularly in patients with obesity/MetS conditions. The potential benefits of metformin use may be secondary to concomitant statin use in this population. Further studies are needed to confirm these results. Statin/metformin rreatment and PCSM among high-risk prostate cancer patients. Medication used Obese or MetS HR (95% CI) + Non-Obese & non-MetS HR (95% CI) + Overall HR (95% CI) + Statin + Metformin (N=1,356) 0.30 (0.07 – 1.27) 0.60 (0.39 – 0.93) 0.57 (0.38 – 0.88) Statin alone (N=4,481) 0.09 (0.01 – 0.64) 0.64 (0.50 – 0.82) 0.60 (0.47 – 0.76) Metformin alone (M=471) --- 0.98 (0.57 – 1.68) 0.92 (0.54 – 1.57) +HR=Hazard Ratios compared to non-users (N= 15,802) and 95% confidence intervals (CI).
Abstract 2155: Acquired tamoxifen resistance sensitises breast cancer cells to bisphosphonates
Authors: Dionysia Lymperatou, Christopher Smith, Wen Guo Jiang, Bronwen Evans, Stephen Hiscox
Journal: Cancer Research (2016)

Abstract Acquisition of resistance to endocrine therapies is a major limiting factor to their clinical effectiveness, resulting in disease relapse and poor prognosis. This may be due in part to the observations that acquired resistance to agents such as tamoxifen is accompanied by a gain in aggressive cellular features likely to promote disease spread and survival at metastatic sites. Bisphosphonates (BPs) are potent antiresorptive drugs used to treat osteoporosis and bone metastasis. Recent evidence also suggests that these agents may possess anti-tumour properties independently of their action on osteoclasts in a range of different tumours including breast cancers resulting in suppression of proliferation and migration and an induction of apoptosis. Here we have explored the potential of the bisphosphonate, zoledronic acid (ZOL) to suppress the aggressive phenotype of acquired endocrine-resistant breast cancer models versus their endocrine-sensitive counterparts. ER+, endocrine-sensitive MCF7 cells and their highly-proliferative, ER+, tamoxifen-resistant (‘TamR’) counterparts were exposed to increasing concentrations of ZOL (1-160μM) for 3 days and changes in growth determined by MTT assay and cell counting. Immunohistochemical analysis of Ki67 confirmed cell growth effects whilst cell cycle analysis was performed using FACS and propidium iodide. Changes in signalling pathways were investigated by Western blotting. The proliferative capacity of TamR cells was greatly suppressed by ZOL in a dose dependent manner in contrast to MCF7, where the effect was minimal (IC50 ± SD: 30 ± 4 μM (TamR) versus 150 ± 15 μM (MCF7); p&amp;lt;0.05). This was confirmed with Ki67 analysis which showed a reduction in Ki67 positivity of 40% (TamR) versus 25% (MCF7); p&amp;lt;0.05. ZOL treatment of TamR cells resulted in a significant loss of cells in G1 phase and an accumulation of the cells in S phase. ZOL treatment of TamR cells also resulted in loss of AKT activity, whilst AKT was unaffected in MCF7 cells. Our data suggests that acquisition of resistance to tamoxifen confers a sensitivity to BPs where treatment of resistant cells with agents such as zoledronic acid results in suppression of proliferation and modulation of AKT signalling. These data suggest that BPs may exert direct anti-tumour effects on breast cancers which have relapsed on endocrine treatment. Citation Format: Dionysia Lymperatou, Christopher Smith, Wen Guo Jiang, Bronwen Evans, Stephen Hiscox. Acquired tamoxifen resistance sensitises breast cancer cells to bisphosphonates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2155.
Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study
Authors: Anita Villani, Ari Shore, Jonathan D Wasserman, Derek Stephens, Raymond H Kim, Harriet Druker, Bailey Gallinger, Anne Naumer, Wendy Kohlmann, Ana Novokmet, Uri Tabori, Marta Tijerin, Mary-Louise C Greer, Jonathan L Finlay, Joshua D Schiffman, David Malkin
Journal: The Lancet Oncology (2016)
Abstract 4670: Combinations of kinase siRNAs potentiates paclitaxel sensitivity in ovarian cancer
Authors: Hailing Yang, Xiaoyan Wang, Ahmed Ahmed, Lakesla Iles, Geoffrey Bartholomeusz, Zhen Lu, Robert C. Bast
Journal: Cancer Research (2016)

Abstract Drug resistance imposes a major obstacle in ovarian cancer treatment. All patients with newly diagnosed ovarian cancer are treated with a combination of paclitaxel and carboplatin. While 70% of ovarian cancers respond to carboplatin, less than 50% respond to paclitaxel. Inhibition of kinases that modulate primary paclitaxel resistance, could enhance response to therapy. A Kinase siRNA library was screened in ovarian cancer cell lines to determine which kinases regulate paclitaxel sensitivity. Among 45 hits from high throughput screening, 14 target proteins (AATK, ACRBP, BMP2K, CHUK, EDN2, IKBKB, ILK, RAPGEF3, RAPGEF4, RFP, SIK2, STK24, STK39 and TBK1) regulated sensitivity to paclitaxel and were differentially expressed or overexpressed in a fraction of ovarian cancers. siRNAs against each of these kinases were tested for the ability to enhance sensitivity to paclitaxel in each of 12 ovarian cancer cell lines that reflected the heterogeneity observed in ovarian cancers including mutations of TP53, BRCA1/2, KRAS, BRAF, PI3K and PTEN. Knockdown of 10 individual genes enhanced paclitaxel sensitivity by at least two folds in different cell lines. A subscreen using combinations of these 14 kinase siRNAs in the six most responsive cell lines were carried out to select pairs of kinase siRNAs which could further potentiate paclitaxel sensitivity. IKBKB and STK39 kinase siRNAs had the greatest activity. We discovered that knockdown of IKBKB and STK39 stabilized microtubules judged by a microtubule fractionation assay and levels of acetylated and detyrosinated tubulin. IKBKB and STK39 kinase siRNAs also induced apoptosis. Double knockdown of microtubule stabilizing kinases IKBKB and STK39 resulted in greater enhancement in microtubule stability and apoptosis, leading to additive sensitization of paclitaxel. Small molecule inhibitors are available for IKBKB. As inhibition drugs become available for STK39, these observations can be translated to the clinic. Citation Format: Hailing Yang, Xiaoyan Wang, Ahmed Ahmed, Lakesla Iles, Geoffrey Bartholomeusz, Zhen Lu, Robert C. Bast Jr.. Combinations of kinase siRNAs potentiates paclitaxel sensitivity in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4670.
Bioequivalence of Biosimilar Tumor Necrosis Factor-α Inhibitors Compared With Their Reference Biologics
Authors: Francine Chingcuanco, Jodi B. Segal, Seoyoung C. Kim, G. Caleb Alexander
Journal: Annals of Internal Medicine (2016)

Biosimilars are of growing clinical, regulatory, and commercial importance.To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-α (TNF-α) inhibitors.PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS from inception through 13 April 2016 and ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, U.S. Food and Drug Administration, and European Medicines Agency from inception through 30 April 2016.Published English-language studies of any size or design that compared the pharmacokinetics, clinical efficacy, adverse events, or immunogenicity of a biosimilar TNF-α inhibitor with a reference biologic in humans.Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality.Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes.Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars.Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-α inhibitors.Johns Hopkins Center of Excellence in Regulatory Science and Innovation. (PROSPERO: CRD42015025262).
A Young Man With Recurrent Coma and Refractory Status Epilepticus
Authors: Zubeda Sheikh, Weizhen Wang, Machteld Hillen
Journal: JAMA Neurology (2016)

A man in his 30s presented with a 5-day history of vomiting, followed by lethargy and confusion. Two years prior, he had been hospitalized with coma with no identifiable precipitant. What is your diagnosis?
First-line crizotinib versus pemetrexed–cisplatin or pemetrexed–carboplatin in patients (pts) with advanced <i>ALK</i>-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014)
Authors: Tony Mok, Dong-Wan Kim, Yi-Long Wu, Benjamin J. Solomon, Kazuhiko Nakagawa, Tarek Mekhail, Enriqueta Felip, Federico Cappuzzo, Jolanda Paolini, Tiziana Usari, Jennifer Tursi, Fiona Helen Blackhall
Journal: Journal of Clinical Oncology (2014)

8002 Background: The efficacy of the oral ALK inhibitor crizotinib as 1st-line treatment for advanced ALK-positive NSCLC compared with standard chemotherapy is unknown. A multicenter, randomized open-label phase III study was conducted to compare the efficacy and safety of crizotinib vs. pemetrexed–platinum chemotherapy (PPC) in this setting. Methods: Between Jan 2011 and Jul 2013, 343 pts with previously untreated advanced non-squamous ALK-positive NSCLC were randomized 1:1 to receive crizotinib 250 mg PO BID (n=172) or PPC (pemetrexed 500 mg/m2 + either cisplatin 75 mg/m2 or carboplatin AUC 5–6; all IV q3w for ≤6 cycles; n=171). Continuation of/crossover to crizotinib after PD (per independent radiologic review) was allowed for pts randomized to crizotinib or PPC, respectively. The primary endpoint was PFS. Secondary endpoints included ORR, OS, safety, and pt-reported outcomes. Results: Proportions of pts in the crizotinib and PPC treatment groups with each stratification factor were 45% and 47% Asians, 94% and 95% with ECOG PS 0/1, and 26% and 28% with previously treated brain metastases, respectively. The study met its primary objective, demonstrating superiority of crizotinib over PPC in prolonging PFS (median 10.9 vs. 7.0 mo; HR: 0.454; 95% CI: 0.346−0.596; P<0.0001). The ORR was significantly higher with crizotinib (74% vs. 45%; P<0.0001). With 68% of pts still in follow-up, a statistically significant improvement in OS was not demonstrated (HR: 0.821; 95% CI: 0.536−1.255; P=0.1804). At time of data cut-off 109 pts on PPC had crossed over to crizotinib. AEs with crizotinib and PPC were consistent with those previously reported in patients with advanced ALK-positive or unselected NSCLC, respectively. The most common all-causality AEs with crizotinib were vision disorder and GI symptoms. Conclusions: First-line crizotinib treatment showed significant improvements in PFS and ORR compared with standard chemotherapy and had an acceptable safety profile. These findings establish crizotinib as the standard of care for pts with previously untreated advanced ALK-positive non-squamous NSCLC. Clinical trial information: 2010-021336-33.
<i>Annals</i> Graphic Medicine - I'd Want a Natural Death
Authors: Nathan Gray
Journal: Annals of Internal Medicine (2016)

Web Exclusives2 August 2016Annals Graphic Medicine - I'd Want a Natural DeathFREENathan Gray, MDNathan Gray, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G16-0002 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G16-0002.Author Information: Dr. Gray is a medical instructor and palliative care physician at Duke University Medical Center.Corresponding Author: Nathan Gray, MD, Duke University Hospital, DUMC Box 2706, Durham, NC 27710; e-mail, nathan.[email protected]duke.edu.Author Contributions: Conception and design: N. Gray.Drafting of the article: N. Gray.Final approval of the article: N. Gray. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 2 August 2016Volume 165, Issue 3Page: W5KeywordsConflicts of interestDisclosureHealth carePalliative care ePublished: 2 August 2016 Issue Published: 2 August 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
IXOA regimen, irinotecan (I), capecitabine (X), oxaliplatin (O), and bevacizumab (A), as first-line therapy for advanced unresectable colorectal cancer (aCRC): Preliminary results.
Authors: Jean Alfred Maroun, Derek J. Jonker, M. Christine Cripps, Rakesh Goel, Timothy R. Asmis, Rachel Anne Goodwin, Nirit Yarom, Horia Marginean
Journal: Journal of Clinical Oncology (2012)

604 Background: IXO showed acceptable toxicities and promising efficacy in a phase I/II study as 1 st -line therapy for aCRC patients (pts). Combination with A might enhance the efficacy of IXO treatment. Methods: The objectives of the study were to evaluate the recommended dose (RD) of IXO regimen when used in combination with A (IXO+A), and to document safety and efficacy of the combination. Starting dose was: I 160mg/m 2 IV d1, X 950mg/m 2 bid PO d2-15, O 100mg/m 2 IV d1, A 7.5 mg/kg iv d1, q3w. IXO regimen dose adjustments were planned in case of therapy-attributed severe toxicities. Results: 23 pts enrolled and evaluable for toxicity, 16M/7F, median age 65 years (range 28-77), PS 0/1/2 in 7/16/0, sites of disease (colon 18/rectum 5) received 288 cycles, median 8 (range 1-40). Gr.4 neutropenia and thromboembolic toxicity in the first 6 pts induced a 15% I and 20% X dose reduction, followed by another 10% I dose reduction in the following 6 pts due to diarrhea and febrile neutropenia. The adjusted regimen with reduced I 25% and X 20% from initial IXO, was considered safe for cohort expansion. Overall Gr.3+ toxicity included: 35% neutropenia, 4% febrile neutropenia, 13% leucopenia, 4% thrombopenia, 7% thromboembolic events, 44% diarrhea, 22% nausea and vomiting, 22% fatigue, 17% dehydration. Two treatment-related deaths (MI and pancolitis) were observed. Among 18 evaluable pts (2 NE, 3 too early for evaluation) response was 12 PR (up to 37 months), 5 SD and one DP. At a median follow-up of 16.5 months, 7 pts have progressed after median 15 months (range 2.5-32.1). Median PFS and OS were not reached. Conclusions: The IXO+A combination required I and X dose adjustment as compared with the initial IXO regimen, with diarrhea, neutropenia and thromboembolic events being the main toxicities. Recruitment continues in an expanded cohort at the newly identified phase II RD: I 125mg/m 2 , X 750mg/m 2 , O 100mg/m 2 , A 7.5 mg/kg. IXO+A shows promising efficacy and acceptable toxicity. Supported by Roche Canada.
Abstract 3706: p53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression following thymidylate synthase (TS) inhibition
Authors: Prashanth Ravishankar Gokare, Niklas Finnberg, Jenny Dai, Maureen Murphy, Wafik El-Deiry
Journal: Cancer Research (2016)

Abstract Nucleotide catabolism by cancer cells can influence malignant behavior and intrinsic resistance to therapy. The rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) contributes to the pharmacokinetics of fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU. Histone H3K9 acetylation marks at the DPYD promoter is diminished concomitantly with reduced expression of DPYD mRNA and protein in a p53-dependent manner. Notably we find that the P72 allele of p53 suppresses DPYD expression more than the R72 p53 allele following 5-FU treatment in mouse embryo fibroblasts. Mechanistic studies reveal inhibition of DPYD expression by p53 is augmented following thymidylate synthase (TS) inhibition by 5-FU, methotrexate (MTX), raltitrexed and siRNA in cancer cells in vitro as well as in mice in vivo. DPYD repression by p53 is dependent on DNA-PK and ATM-signaling since pharmacologic targeting of these kinases reverses the transcriptional repression of DPYD by p53. Mice lacking p53 in their livers have increased conversion of 5-FU to 5-FUH2 in plasma and elicit a diminished 5-FU therapeutic response in syngeneic colorectal tumor xenografts as compared to littermates with an intact p53 allele consistent with increased DPYD-activity. Our data suggest that p53 plays an important role in controlling pyrimidine catabolism through its ability to regulate DPYD, particularly following metabolic stress imposed by nucleotide imbalance. The findings have implications for the toxicity and efficacy of the cancer therapeutic 5-fluorouracil. Citation Format: Prashanth Ravishankar Gokare, Niklas Finnberg, Jenny Dai, Maureen Murphy, Wafik El-Deiry. p53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression following thymidylate synthase (TS) inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3706.
Effects of Organizational Characteristics on Outcomes and Resource Use in Patients With Cancer Admitted to Intensive Care Units
Authors: Marcio Soares, Fernando A. Bozza, Luciano C.P. Azevedo, Ulysses V.A. Silva, Thiago D. Corrêa, Fernando Colombari, André P. Torelly, Pedro Varaschin, William N. Viana, Marcos F. Knibel, Moyzés Damasceno, Rodolfo Espinoza, Marcus Ferez, Juliana G. Silveira, Suzana A. Lobo, Ana Paula P. Moraes, Ricardo A. Lima, Alexandre G.R. de Carvalho, Pedro E.A.A. do Brasil, Jeremy M. Kahn, Derek C. Angus, Jorge I.F. Salluh
Journal: Journal of Clinical Oncology (2016)

To investigate the impact of organizational characteristics and processes of care on hospital mortality and resource use in patients with cancer admitted to intensive care units (ICUs).We performed a retrospective cohort study of 9,946 patients with cancer (solid, n = 8,956; hematologic, n = 990) admitted to 70 ICUs (51 located in general hospitals and 19 in cancer centers) during 2013. We retrieved patients' clinical and outcome data from an electronic ICU quality registry. We surveyed ICUs regarding structure, organization, staffing patterns, and processes of care. We used mixed multivariable logistic regression analysis to identify characteristics associated with hospital mortality and efficient resource use in the ICU.Median number of patients with cancer per center was 110 (interquartile range, 58 to 154), corresponding to 17.9% of all ICU admissions. ICU and hospital mortality rates were 15.9% and 25.4%, respectively. After adjusting for relevant patient characteristics, presence of clinical pharmacists in the ICU (odds ratio [OR], 0.67; 95% CI, 0.49 to 0.90), number of protocols (OR, 0.92; 95% CI, 0.87 to 0.98), and daily meetings between oncologists and intensivists for care planning (OR, 0.69; 95% CI, 0.52 to 0.91) were associated with lower mortality. Implementation of protocols (OR, 1.52; 95% CI, 1.11 to 2.07) and meetings between oncologists and intensivists (OR, 4.70; 95% CI, 1.15 to 19.22) were also independently associated with more efficient resource use. Neither admission to ICUs in cancer centers compared with general hospitals nor annual case volume had an impact on mortality or resource use.Organizational aspects, namely the implementation of protocols and presence of clinical pharmacists in the ICU, and close collaboration between oncologists and ICU teams are targets to improve mortality and resource use in critically ill patients with cancer.