tbuckley/cabot-search huggingface dataset:
Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial
Authors: John R Petrie, Nishi Chaturvedi, Ian Ford, Martijn C G J Brouwers, Nicola Greenlaw, Therese Tillin, Irene Hramiak, Alun D Hughes, Alicia J Jenkins, Barbara E K Klein, Ronald Klein, Teik C Ooi, Peter Rossing, Coen D A Stehouwer, Naveed Sattar, Helen M Colhoun, H Nickerson, O Lou, S Dutta, J Haw, C Anderson, S Kean, E Thomson, L Gillespie, J Gibb, N Greenlaw, A Keech, A Jenkins, K March, S Williams, E Coady, M Bots, J Dreyer, T Jan, K Sheffy, R Lusky, S Peleg, A Shore, D Carty, P Donnan, M Witham, A Adler, E Lonn, P Rauchhaus, R Lindsay, M Brouwers, J Van-Melckebeke, L Gillespie, T Hamill, L Cuthbertson, A Murray, L Jolly, E Miller, J Hair, A Bell, S Carmichael, E Douglas, P Surtees, E Dinnett, J Allan, C Watson, M McLaughlin, G Brindley, E Smillie, D Motherwell, S MacDonald, P Ellis, D Stuart, M Travers, S Brearley, L Greig, P Colman, A Nankervis, S Forulanos, D West, S Vaughan, M Bjorasen, J Donlan, J Vrazas, D O'Neal, J Horsburgh, H Pater, S Kent, S Twigg, G Fulcher, R Denner, A Piotrowicz, A Januszewski, A Coy, T Paul, C McDonald, S Tereschyn, N Schmidt, M Weingert, H Heard, S Burke, TC Ooi, H Lochnan, A Sorisky, E Keely, J Malcolm, J Maranger, C Favreau, S Petherick, K Boles, P Rossing, TW Hansen, S Lund, B Hemmingsen, N Thorogood, K Green, T Robinson, K Abouglilia, D Nayman, C Miller, R Warren, K Aizawa, M Balasubramani, S Toth, K Harvey, G Birch, S Atkin, T Sathyapalan, A James, Z Javed, J Wilding, B Martin, S Birch, A Wilcox, N Watson, N Oliver, N Jugnee, M Rutter, T Turgut, A Shaju, S Yau, S Subin, M Walker, D Wake, C Miller, A Millward, P Chong, M Hibbert, J George, N Schaper, J Pinxt, J op het Roodt, Sam Phillips, L Murray, L Sleigh, A Collier, LE Sit, K Allan, J Cook, K Campbell, L Hodge, G Leese, G Reekie, A Jaap, A Sudworth, A White, J McKnight, L Steven, G McKay, A Llano, G Currie, E Lennon, J Johnstone, K Shields
Journal: The Lancet Diabetes & Endocrinology (2017)
Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor
Authors: Michael Fralick, Sebastian Schneeweiss, Elisabetta Patorno
Journal: New England Journal of Medicine (2017)

A study that assessed the risk of diabetic ketoacidosis after the initiation of SGLT2 inhibitor therapy showed nearly twice the risk as with a DPP4 inhibitor.
Effect of trastuzumab emtansine (T-DM1) on autologous platelet kinetics.
Authors: Vijyakrishna Gadi, Jill Corson, Arianne Cundy, Shawn Bailey, Esther Pellham, Todd Christoffel, Irena Gettinger, Jeffrey Barroso, Sherrill Slichter
Journal: Journal of Clinical Oncology (2017)

e12521 Background: T-DM1 treatment results in Grade 3-4 thrombocytopenia in 8%-13% (1.4% with clinically significant bleeding). Prior in vitro studies reported T-DM1 inhibition of megakaryocyte maturation as the cause of decreased platelet production. The current study was initiated to evaluate the cause of thrombocytopenia in patients. Methods: Patients with HER2-positive metastatic breast cancer (N = 10) were enrolled in this Phase 1 study. 111 In radiolabeled autologous platelet recoveries and survivals as well as serial platelet counts, bleeding time assays, platelet aggregation responses to epinephrine, adenosine diphosphate, collagen, arachidonic acid, ristocetin, and thromboxane were performed at baseline and during two consecutive cycles (C) of the drug (3.6mg/kg IV q3weeks). Results: Platelet nadir occurred on days (D) 7, 8, or 9 post-T-DM1 in C1 and at D5-6 in C2. Average nadir counts (% baseline) in C1 and C2 were 116,000/µl (52 ±22%) and 117,000/µl (48 ±31%), respectively, with return to baseline by D15 in both cycles. Autologous 111 In-labeled platelet recoveries averaged 64 ±10%, 65 ±12%, and 65 ±12% at baseline, C1 and C2, respectively. Baseline platelet survival averaged 8.8 (±1.1) days but progressively shortened to 5.4 (±1.6) days during C1 and 4.6 (±1.0) days during C2 (p &lt; 0.001 compared to baseline for both cycles). Bleeding times were appropriate for the corresponding platelet count throughout both cycles. Aggregation responses to all agonists decreased during the study, more in C2 than in C1. Conclusions: Following T-DM1 administration, platelet kinetic measurements demonstrated statistically significant progressive decreases in platelet survivals from normal baseline values (decreased survivals were observed in all patients treated on study). In distinction to published in vitro studies, these unexpected results indicate a direct toxic effect of T-DM1 on patients’ autologous circulating platelets. In addition, autologous aggregation responses were decreased, suggesting drug-induced platelet dysfunction. Clinical trial information: NCT01816035.
RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus
Authors: Xue-Hai Liang, Hong Sun, Joshua G. Nichols, Stanley T. Crooke
Journal: Molecular Therapy (2017)

RNase H1-dependent antisense oligonucleotides (ASOs) are active in reducing levels of both cytoplasmic mRNAs and nuclear retained RNAs. Although ASO activity in the nucleus has been well demonstrated, the cytoplasmic activity of ASOs is less clear. Using kinetic and subcellular fractionation studies, we evaluated ASO activity in the cytoplasm. Upon transfection, ASOs targeting exonic regions rapidly reduced cytoplasmically enriched mRNAs, whereas an intron-targeting ASO that only degrades the nuclear pre-mRNA reduced mRNA levels at a slower rate, similar to normal mRNA decay. Importantly, some exon-targeting ASOs can rapidly and vigorously reduce mRNA levels without decreasing pre-mRNA levels, suggesting that pre-existing cytoplasmic mRNAs can be cleaved by RNase H1-ASO treatment. In addition, we expressed a cytoplasm-localized mutant 7SL RNA that contains a partial U16 small nucleolar RNA (snoRNA) sequence. Treatment with an ASO simultaneously reduced both the nuclear U16 snoRNA and the cytoplasmic 7SL mutant RNA as early as 30 min after transfection in an RNase H1-dependent manner. Both the 5′ and 3′ cleavage products of the 7SL mutant RNA were accumulated in the cytoplasm. Together, these results demonstrate that RNase H1-dependent ASOs are robustly active in both the cytoplasm and nucleus. RNase H1-dependent antisense oligonucleotides (ASOs) are active in reducing levels of both cytoplasmic mRNAs and nuclear retained RNAs. Although ASO activity in the nucleus has been well demonstrated, the cytoplasmic activity of ASOs is less clear. Using kinetic and subcellular fractionation studies, we evaluated ASO activity in the cytoplasm. Upon transfection, ASOs targeting exonic regions rapidly reduced cytoplasmically enriched mRNAs, whereas an intron-targeting ASO that only degrades the nuclear pre-mRNA reduced mRNA levels at a slower rate, similar to normal mRNA decay. Importantly, some exon-targeting ASOs can rapidly and vigorously reduce mRNA levels without decreasing pre-mRNA levels, suggesting that pre-existing cytoplasmic mRNAs can be cleaved by RNase H1-ASO treatment. In addition, we expressed a cytoplasm-localized mutant 7SL RNA that contains a partial U16 small nucleolar RNA (snoRNA) sequence. Treatment with an ASO simultaneously reduced both the nuclear U16 snoRNA and the cytoplasmic 7SL mutant RNA as early as 30 min after transfection in an RNase H1-dependent manner. Both the 5′ and 3′ cleavage products of the 7SL mutant RNA were accumulated in the cytoplasm. Together, these results demonstrate that RNase H1-dependent ASOs are robustly active in both the cytoplasm and nucleus.
Which is related baseline biomarker value or biomarker change to early recurrence in ER positive HER2-negative breast cancer with neoadjuvant endocrine therapy?
Authors: Daishu Miura, Masami Kadowaki, Nobuko Tamura, Hidetaka Kawabata, Keiichi Kinowaki, Takeshi Fujii
Journal: Journal of Clinical Oncology (2015)

e11569 Background: Current approaches of neoadjuvant endocrine therapy (NAET) are focusing on biomarker analysis of the diagnostic specimens however inadequate response occurs in 5-10%of patients treated. Although it has been reported woman whose Ki67 inadequately decrease or increase for aromatase inhibitor (AI) treatment may interpret primary AI resistance, much less is known about its prognosis. A pilot study was conducted to investigate the significances of baseline biomarker values and biomarker changes for short term NAET (letrozole or exemestane) and also investigate the prognosis and mechanisms of AI resistance. Methods: Totally 64 postmenopausal ER positive Her2 negative stage 1-3 breast cancers receiving LET or EXE until surgery (median 22 days) were enrolled. All cases were proved strong ER positivity by IHC. After excluding adjuvant chemotherapy, no continuation of the AI more than 2 years of adjuvant therapy, and no having high-quality of mRNA, 53 cases (LET 25, EXE 28) were analyzed with pre- and post-treatment mRNA expression of ER related 60 biomarkers using QuantiGene Assay. We investigate the relationship between breast cancer recurrence and biomarkers and compared with 2 AIs. Results: Clinical characteristics between 25 cases of LET and 28 of EXE were well balanced. Breast cancer recurrence was observed in 2 cases of LET and 3 of EXE for 4.9 years of median follow. Despite increased Ki67 mRNA in 4 of LET and 3 of EXE after AI, recurrence was found in one case out of 7. Although several genes including Ki67 and PR significantly changed after AIs, there were no correlations between two AIs and between the recurrence and the changes of biomarkers. Whereas significant low basal expression of ER related genes (ESR1, PR, Bcl2, SCUBE2), cell cycle related genes (CDK4, CCND1, p27, p16), and signal related genes (Her2, Her3, IGF1R, MAPK1, MAPK8, PIK3CA, NFkB) were found in recurrent cases. Conclusions: Early recurrence of ER positive Her2 negative breast cancer with AI treatment is strongly correlated with basal biomarker values than its changes. Further investigation is warranted to understand the mechanisms of drug resistance and biomarker changes.
Phase Ib study of heat shock protein 90 inhibitor, onalespib in combination with paclitaxel in patients with advanced, triple-negative breast cancer (NCT02474173).
Authors: Robert Wesolowski, Maryam B. Lustberg, Raquel E. Reinbolt, Jeffrey Bryan VanDeusen, Sagar D. Sardesai, Nicole Olivia Williams, Anne M. Noonan, Shabana Jaynul Dewani, Ming Poi, Debbie Wilson, Michael R. Grever, Julie Stephens, Shannon Puhalla, Aju Mathew, William Edgar Carson, Bhuvaneswari Ramaswamy
Journal: Journal of Clinical Oncology (2017)

TPS1127 Background: Heat shock protein 90 (HSP90) is a molecular chaperone which is necessary for proper folding and stabilization of proteins. Client proteins of HSP90 include many oncogenic proteins known to be over-activated in triple negative breast cancer such as AKT, EGFR, members of RAS/MAPK signaling pathway and androgen receptor. High expression of HSP90 in breast cancer has been associated with poor outcome. In addition, over-expression of HSP90 client proteins such as AKT and c-RAF has been implicated in paclitaxel resistance. Onalespib (AT13387) is a synthetic non-ansamycin small molecule that acts as an inhibitor of HSP90 by binding to the amino terminal of the protein and has dissociation constant (Kd) of 0.71 nM. Methods: Patients with inoperable or metastatic, triple negative or &lt; 10% hormone receptor positive breast cancer are treated with onalespib and paclitaxel on days 1, 8, 15 every 28 days. Paclitaxel is given at a standard dose of 80 mg/m2 while the dose of onalespib is gradually increased using standard 3+3 design (see table). In order to assess the effect of each drug on pharmacokinetics of the other drug, onalespib is given on day -7 prior to cycle 1 and skipped on day 1 of cycle 1 during which paclitaxel is administered alone. The primary objective of the study is to determine recommended phase II dose and assess the toxicity profile of the combination. The secondary objectives include pharmacokinetic of each agent. Overall response rate, response duration and progression-free survival will also be assessed. The study is currently enrolling patients to dose level 2. Clinical trial information: NCT02474173. [Table: see text]
Is androgen receptor useful to predict the efficacy of anti-estrogen therapy in advanced breast cancer?
Authors: Andrea Rocca, Giuseppe Bronte, Sara Ravaioli, Maurizio Puccetti, Maria Maddalena Tumedei, Emanuela Scarpi, Roberta Maltoni, Samanta Sarti, Lorenzo Cecconetto, Lucia Bedei, Anna Fedeli, Daniele Andreis, Elisabetta Pietri, Daniele Calistri, Dino Amadori, Sara Bravaccini
Journal: Journal of Clinical Oncology (2017)

1042 Background: The androgen receptor (AR) is widely expressed in breast cancers but its role in estrogen receptor (ER)-positive tumors is still controversial. However, the AR/ER ratio may impact prognosis and the response to antiestrogen endocrine therapy (ET). Methods: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced breast cancer (ABC). We evaluated patients treated with first-line ET (2002–2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with &gt; 2 lines of chemotherapy. ER, progesterone receptor (PgR), Her2, Ki67 and AR expression was determined by immunohistochemistry. A cut-off of &lt; 1% immunostained cells was used to categorize AR expression. AR expression was analyzed in relation to the other conventional biomarkers (ER, PgR, Her2 and Ki67), best response (CR, PR, SD, PD), and time to progression (TTP) (months). TTP was estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios and their 95% confidence intervals (95% CI) were estimated using the Cox regression model. The Chi-square test was used to evaluate correlations between categorical variables and best response. p values &lt; 0.05 were considered statistically significant. Results: Of the 102 evaluable patients (93% were treated with an aromatase inhibitor), biomarkers were assessed in primary tumors in 70 cases, in metastases in 49 and in 17 in both). Median TTP was 17 months (95% CI 14-21.5, median follow-up 75 months). The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR expression. Differences in TTP according to AR status were not statistically significant. AR/PgR ≥ 0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.030). AR status in primary tumors or metastases was not associated with PD as best response. In contrast, Ki67 &gt; 20% and PgR &lt; 10% showed a significant association with PD as best response. Using a cut off of ≤10% for AR expression, results did not change. Conclusions: AR expression does not appear to be useful to predict the efficacy of ET in ABC. Ki67 and PgR exert a greater impact on the efficacy of hormone therapy than AR.
Erratum: CEP-7055: A Novel, Orally Active Pan Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinases with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models (Cancer Research (September 15, 2003) (5978-5991))
Authors: Bruce Ruggeri, Jasbir Singh, Diane Gingrich, Thelma Angeles, Mark Albom, Shi Yang, Hong Chang, Candy Robinson, Kathryn Hunter, Pawel Dobrzanski, Susan Jones-Bolin, Sonya Pritchard, Lisa Aimone, Andres Klein-Szanto, Jean Marc Herbert, Francoise Bono, Paul Schaeffer, Pierre Casellas, Bernard Bourie, Roberto Pili, John Isaacs, Mark Ator, Robert Hudkins, Jeffrey Vaught, John Mallamo, Craig Dionne
Journal: Cancer Research (2003)
Cetuximab with or without chemotherapy for recurrent, unresectable squamous cell carcinoma of the skin (SCCS).
Authors: Kalyan Nadiminti, Ryan Shao, Gerald H. Clamon, Ahmad Mouhamad Wehbe
Journal: Journal of Clinical Oncology (2013)

9090 Background: With an increasing aging population and a growing number of people with organ transplant on immune suppression, patients presenting with locally advanced, unresectable and metastatic SCCS are on the rise. Options of therapy are limited to platinum or taxane doublets but the tolerability of these regimens is poor. Data regarding use of cetuximab in advanced SCCS is scarce and consists of a few case series and one phase II trial. The purpose of this study is to evaluate the use of cetuximab alone or in combination with chemotherapy in patients with SCCS treated at the University of Iowa Hospitals (UIHC). Methods: Patient data was compiled through medical record review of all patients diagnosed with locally recurrent, unresectable or metastatic SCCS seen at UIHC and treated with cetuximab alone or in combination with chemotherapy. Pathology was centrally reviewed. Results: A total of nine patients with SCCS received cetuximab as part of a definitive or palliative therapy with a loading dose of 400 mg/m2 followed by weekly 250mg /m2.Median age of patients is 64. Four patients had locally recurrent or unresectable disease, and five had distant metastases. Three patients had prior history of organ transplant. Chemotherapy included carboplatin AUC 5 with 5 fluorouracil 1000mg/m2/day for four days in two patients and weekly paclitaxel 80mg/m2 in four patients. One patient received concurrent definitive radiation with 6600 cGy. In total, six patients completed at least 6 weeks of cetuximab. All these patients showed clinical improvement in pain, tumor ulcer and bleeding as compared to pretreatment. Median time to disease progression after stopping treatment was 3 months. Three patients could not complete 6 weeks of cetuximab due to disease progression. The most common side effect was skin rash and hypomagnesemia. Conclusions: Cetuximab alone or in combination with chemotherapy is well tolerated and does show promise in treatment of patients with unresectable or metastatic SCCS. Most common side effect was skin rash. A larger trial with longer follow up is warranted to establish the role of cetuximab and an optimal combination therapy in improving quality of life in this patient population.
Effects of lifestyle and diet as modifiers of risk of breast cancer (BC) in BRCA1 and BRCA2 carriers.
Authors: Marina Pollan, Asunción Torres, Teresa Ramon Y Cajal, Gemma Llort, Adela Castello, David Fisas, Carmen Yague, Consol Lopez, Maria Teresa Leon, Marina Pollan
Journal: Journal of Clinical Oncology (2017)

1505 Background: Mutations in the BRCA1/2 genes confer a high lifetime risk of BC. Penetrance varies among populations and individuals suggesting that non-genetic factors may modify the inherited risk. Knowledge of modifiable factors will help to develop preventive strategies. Methods: Information on physical activity (PA) (current PA and in the adolescence) and smoking was collected in 892 women (W) with a BRCA1/BRCA2 germ-line mutation (582 with BC, 45,62% BRCA2) from 279 families, followed at three Spanish Genetic Counseling Units, 481of these W also answered a food frequency questionnaire. Participants gave their consent and the study was approved by the ethics committee. The association between BC, lifestyle factors and dietary patterns (Mediterranean and Western) associated with BC were studied using logistic regression. Huber-White robust estimators of variance were employed to take into account correlations between family members. Age, menopausal status, specific mutated gene, BMI, parity and oral contraception were included as co-variables. BC was classified as HR+/+,- or HR-. Results: W who did PA daily had half the risk of BC than sedentary W (OR:0,53;p=0,043 for current PA;OR:0,40;p=0,007 for PA in the adolescent) and no differences were observed between BRCA1 and BRCA2 carriers. Also, W who daily exercised in both periods had a reduction of their BC risk (OR:0,22;p&lt;0,001). The effect of PA was particularly important among premenopausal W (p-het&lt;0,05). PA in the adolescent decreased the risk of all type of tumors. Nevertheless, alcohol intake, smoking habit and type of diet, did not significantly modify BC risk in this BRCA W. Conclusions: Our preliminary data suggest a clear reduction in BC risk among BRCA1/2 carriers who exercise regularly, mainly during the adolescence, and could be considered as potential modifiable factor for BC prevention in these group of W.
Use of serial multi-template liquid biopsies in triple negative breast cancer monitoring.
Authors: Paul Y. Song, Jill Simmons, Paul W. Dempsey, Erich Klem, Chris Carter, Shahram Tahvilian, Brian Scollick, William Strauss
Journal: Journal of Clinical Oncology (2017)

1091 Background: Triple negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer in which up to 1/3 of all patients will relapse early and distantly. There remains no proven method to monitor and detect early recurrence. This study examines the utility of serial liquid biopsies using a multi-template approach (identification and analysis of cell-free DNA (cfDNA) and circulating tumor cells (CTCs)) as a solution. Methods: 210 patients (average 53 yrs.) with confirmed diagnosis of TNBC, within 3 years of completion of therapy (mean 25 mos.), and in full remission were enrolled. Liquid biopsies were performed quarterly to look for cancer specific genomic mutations not seen in germ line controls, but in cfDNA and CTCs using a custom 27-gene breast cancer panel. Prior validation of our gene panel demonstrated a false positive rate of 0.001-0.0007% in normal cfDNA and cell-based controls. Results: Each subject had on average 3.0 serial samples collected to date. 169 patients (80.4%) had evidence of mutations in at least one sample. Seventy-five percent of cfDNA and 36% of CTC samples examined have been found to bear mutations. The total number of samples with orthogonally (either between template or between draws) confirmed signal was 16.9%. Seven patients (3.3%) have developed documented evidence of recurrence, one in the axilla and the others with visceral/distant metastases. Of the patients that have recurred, all had a persistent mutation on consecutive blood draws or evidence of genomic mutations in both cfDNA and CTCs. Conclusions: The majority of TNBC patients in our study post-treatment were found to have genomic mutations on at least one liquid biopsy sample – either cfDNA or CTC. But, very few had a persistent presence of mutations in subsequent samples and 96.7% of our patients have remained NED. Unlike patients who remained NED, patients who recurred displayed persistent evidence of mutations on serial draws or in both cfDNA and CTC samples. To date our recurrence rate is lower than predicted. This study highlights the need for serial monitoring using a multi-template approach to better fully understand patient specific tumor biology and kinetics. The trial is ongoing. Clinical trial information: NCT02639832.